Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

†Not commercially available in Canada.

Category:

Note: All of these medications have analgesic, antipyretic, and anti-inflammatory actions; however, indications for specific agents may vary because of lack of specific testing and/or clinical-use data as well as the toxicity of the individual nonsteroidal anti-inflammatory drug (NSAID). Clinically, most of these agents are used to treat a variety of painful and/or inflammatory conditions, both rheumatic and nonrheumatic, even though the specific uses are not listed in U.S. or Canadian product labeling. {223}6

[Arthritis, psoriatic]1—Diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, phenylbutazone, and tolmetin are used in the treatment of psoriatic arthritis. {321}8

[Reiter"s disease]1—Indomethacin is used in the treatment of Reiter"s disease. {321}7

[Rheumatic complications associated with Paget"s disease of bone]1— Indomethacin is used in the treatment of this condition. {321}6
Although NSAIDs may be required for relief of [ rheumatic complications occurring in association with systemic lupus erythematosus (SLE)]1 , {321}5{321}4 extreme caution is recommended because patients with SLE may be predisposed toward NSAID-induced central nervous system (CNS) and/or renal toxicity. {321}3 Several NSAIDs, including ibuprofen, {321}2{321}1{321}0{322}9 sulindac, {322}8 and tolmetin, {322}7 have been shown to cause serious adverse effects, including aseptic meningitis, in patients with SLE. In addition, ibuprofen (although a causal relationship has not been established), {322}6 meclofenamate, {322}5 and phenylbutazone {322}4 have rarely been reported to cause an SLE-like syndrome and/or to exacerbate pre-existing SLE.

NSAIDs do not affect the progressive course of some forms of rheumatic disease. Some patients with rheumatoid arthritis may need additional treatment. {322}3
Pain (treatment)—Diclofenac, {322}2{322}1 diflunisal, {322}0{213}9{213}8{213}7 etodolac, {213}6 fenoprofen1 , {213}5{213}4 floctafenine, {213}3{213}2 ibuprofen, {213}1{213}0{213}9{213}8{213}7{213}6{213}5 ketoprofen, {213}4{213}3{213}2 meclofenamate, {213}1{213}0 mefenamic acid, {48}9{48}8{48}7{48}6 and naproxen {48}5{48}4{48}3{48}2{48}1{48}0{213}9 are indicated for relief of mild to moderate pain, especially when anti-inflammatory actions may also be desired, e.g., following dental, obstetric, or orthopedic surgery, and for relief of musculoskeletal pain due to soft tissue athletic injuries (strains or sprains). Only immediate-release dosage forms are recommended for relief of acute pain because of their more rapid onset of action relative to delayed-release or extended-release dosage forms. {213}8
—Mefenamic acid is indicated for relief of mild to moderate pain when therapy will not exceed 1 week. {213}7{213}6
—Those NSAIDs indicated for relief of pain are also recommended for relief of mild to moderate bone pain caused by metastatic neoplastic disease. However, careful patient selection is necessary, especially in patients receiving chemotherapy, because of the potential gastrointestinal or renal toxicity and the platelet aggregation–inhibiting actions of these medications. {213}5

Gouty arthritis, acute (treatment) or
[Calcium pyrophosphate deposition disease, acute (treatment)]1{213}4—[Diclofenac]1, {213}3 [diflunisal]1 , {213}2 [etodolac] , {213}1 [fenoprofen]1 , {213}0 floctafenine1 , {48}9 [ibuprofen]1 , {48}8 indomethacin, {48}7{48}6{48}5{48}4 [ ketoprofen]1 , {48}3 [ meclofenamate] , {48}2 [ mefenamic acid]1 , {48}1 naproxen1 , {48}0{213}9{213}8 phenylbutazone, {213}7{213}6{213}5 [piroxicam]1 , {213}4 and sulindac {213}3{213}2{213}1{213}0 are indicated [or used ] for relief of the pain and inflammation of acute gouty arthritis and [ acute calcium pyrophosphate deposition disease (pseudogout; chondrocalcinosis articularis; synovitis, crystal-induced)]1 . Only immediate-release dosage forms are recommended for relief of acute attacks because of their more rapid onset of action relative to delayed-release or extended-release dosage forms. {213}9
—[Long-term prophylactic use of an NSAID may decrease the incidence or severity of recurrent acute gout attacks, especially during the early months of antihyperuricemic therapy. {213}8 The NSAIDs do not correct hyperuricemia (although diclofenac, {213}7 diflunisal, {213}6 etodolac, {213}5 oxaprozin, {213}4{213}3 and phenylbutazone {213}2 have some uricosuric activity) and do not eliminate the need for administration of an antihyperuricemic agent for the long-term management of chronic gout. {213}1 Colchicine is the recommended agent for preventing acute gout attacks because, in low (prophylactic) doses, it is less toxic for long-term use than NSAIDs. {213}0 NSAIDs (other than phenylbutazone, which is not recommended for long-term treatment) {213}9 should be used only for patients unable to tolerate even prophylactic doses of colchicine. {213}8]

Inflammation, nonrheumatic (treatment)—Most of the NSAIDs are indicated [or used] in the treatment of painful nonrheumatic inflammatory conditions, such as
Athletic injuries
Bursitis
Capsulitis
Synovitis
Tendinitis; or
Tenosynovitis—[Flurbiprofen is indicated for relief of bursitis, tendinitis, and soft tissue injuries.] {213}7{213}6 Indomethacin1{213}5{213}4 and sulindac {213}3{213}2{213}1{213}0 are indicated for treatment of bursitis and/or tendinitis of the shoulder. Naproxen {140}9{140}8{140}7{140}6{140}5 is indicated for treatment of bursitis and/or tendinitis of any joint. Tenoxicam is indicated for treatment of tendinitis, bursitis, and periarthritis of the shoulders or hips. {140}4 [Other NSAIDs, especially those approved by U.S. and/or Canadian regulatory agencies for relief of pain, are also used in the treatment of these and other painful inflammatory conditions.]1{140}3

[Fever, due to malignancy (treatment) ]1—Indomethacin (rapidly acting dosage forms only) is used to reduce fever in patients with Hodgkin"s disease, other lymphomas, and hepatic metastases of solid tumors. Indomethacin should be used only after aspirin and acetaminophen have proven ineffective. If antipyretic therapy at an adequate dosage is not effective within 48 hours, indomethacin should be discontinued. {213}8

Hypermenorrhea (treatment)—Meclofenamate is indicated for treatment of idiopathic excessive menstrual bleeding. The absence of an underlying pathologic condition should be verified before meclofenamate therapy is instituted. {216}2 [NSAIDs that are used for relief of dysmenorrhea (see Dysmenorrhea , above) may also decrease excessive menstrual blood loss caused by an intrauterine device in addition to relieving other symptoms.]1{216}1

[Headache, vascular (prophylaxis) ]1or
[Headache, vascular (treatment)]1—Diclofenac, diflunisal, etodolac, fenoprofen, floctafenine, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, and naproxen are used to relieve (when taken at the first sign of onset) migraine headache or other vascular headaches. Fenoprofen, ibuprofen, indomethacin, and naproxen are also used chronically to prevent recurrence of such headaches. Fenoprofen, ibuprofen, indomethacin, mefenamic acid, and naproxen may also be taken prior to and during menstruation to prevent migraine associated with menstruation. {216}0

[Bartter"s syndrome (treatment)]1—Indomethacin is used in the treatment of Bartter"s syndrome. However, its use in this condition has been associated with adverse effects, including pseudotumor cerebri. Because long-term therapy is required, it has been suggested that other, less toxic, NSAIDs may be suitable alternatives to indomethacin. {216}9

[Pericarditis]1—Indomethacin (rapidly acting dosage forms only) is used to relieve pain, fever, and inflammation associated with pericarditis. {216}8Unaccepted
Except in the treatment of ankylosing spondylitis, for which it is a treatment of choice, and Bartter"s syndrome, indomethacin is not recommended as initial therapy because of its potential for causing severe side effects. {216}7 Also, although indomethacin, like other NSAIDs, has analgesic and antipyretic activity, it should not be used indiscriminately (because of its toxicity) to relieve pain or reduce fever. {216}6

Phenylbutazone is not recommended as initial therapy for any indication. Because of its potential for causing severe side effects, including agranulocytosis and aplastic anemia, it should be used only after less toxic treatments (including other, less toxic, NSAIDs) have been found ineffective. In many countries, phenylbutazone is approved only for treatment of severe ankylosing spondylitis unresponsive to other NSAIDs. Use of phenylbutazone to relieve the pain and inflammation of acute painful shoulder (i.e., peritendinitis, capsulitis, or bursitis of that joint) is no longer FDA-approved. It is strongly recommended that use of phenylbutazone be restricted to short-term treatment of severe flares of rheumatic disease, gout, or calcium pyrophosphate deposition disease. {216}5{216}4{216}31 Not included in Canadian product labeling.

* To albumin.† Taken on an empty stomach.‡ Taken with food.§ Absorption not affected by antacids, specifically: For fenoprofen, ibuprofen, ketoprofen, meclofenamate, piroxicam, sulindac, tolmetin—Aluminum- and magnesium-containing; For tiaprofenic acid—Aluminum-containing# May be increased in geriatric patients (For flurbiprofen, geriatric females only).** Decreased by 40% in patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis.†† Decrease to 37 mcg/mL demonstrated in obese patients, probably because volume of distribution increased.‡‡ Failure to retain suppository in rectum for one full hour may be responsible for incomplete absorption.§§ Bioavailability 73–93% of that achieved with oral administration.## Mean 8 hours in patients with hepatic cirrhosis. Not significantly different in geriatric patients than in younger adults.*** Administration of a second 1000-mg dose 12 hours after an initial 1000-mg dose produced peak concentrations of ±71 mcg/mL. Peak concentrations are significantly decreased (to as low as 18 mcg/mL) in patients with hepatic cirrhosis.††† May be increased by concurrent administration of sodium bicarbonate.‡‡‡ Similar values reported with administration of 500-mg tablets to adults and with administration of 5 mg/kg of oral suspension to children 5 to 16 years of age with juvenile arthritis.§§§ Increased to 70.7 mcg/mL by concurrent administration with antacid.### May be increased to 2 to 3 weeks if elimination half-life is greatly prolonged.**** May be increased if elimination half-life is greatly prolonged and/or renal function is impaired.†††† May be increased to 4 to 7 hours in patients with alcoholic hepatic disease.

Hepatic, with extensive first-pass metabolism. 35–38% of a 1000-mg dose metabolized to the active substance 6-MNA, which is further metabolized hepatically; bioavailability of 6-MNA decreased in patients with severe hepatic function impairment

* Dialyzable.† Some metabolites may be active.‡ Not dialyzable.§ In patients with renal function impairment. GFR=glomerular filtration rate in mL per minute, when specified.# Reason for prolonged half-life is unclear because only small amounts are excreted unchanged. It has been proposed that biliary excretion of metabolites with subsequent hydrolysis to, and reabsorption of, the parent compound may occur in renal failure. Alternatively, slower renal excretion may permit hydrolysis of an unstable metabolite to the parent compound.** Excretion (renal plus biliary/fecal) complete within 24 hours.†† Subject to large interindividual variation, possibly because of differences in enterohepatic circulation and subsequent reabsorption.‡‡ Undergoes extensive enterohepatic circulation.§§ Acyl-glucuronide conjugate is unstable; in patients with renal function impairment, this conjugate may accumulate and be deconjugated to the parent compound.## Higher values for the extended-release dosage forms reflect prolonged absorption. In geriatric patients, values for the capsules and the extended-release capsules are prolonged by 26% and 54%, respectively. Also, values for the capsules may be prolonged to 3 hours in patients with mild renal function impairment and to 5 to 9 hours in patients with moderate to severe renal function impairment.*** Enterohepatic recirculation has been proposed to account for elimination of the other 40% of the dose; however, studies to confirm this possibility have not been done.††† Hydroxymethyl metabolite has anti-inflammatory activity approximately 20% of that of the parent compound.‡‡‡ In geriatric patients, in whom values are especially subject to substantial interpatient variability; values as high as 74 hours have been measured. Also, increased to about 39 hours in patients with creatinine clearances <30 mL/minute/1.73 cubic meters of body surface area, but not in patients with lesser degrees of renal function impairment or in patients receiving hemodialysis.§§§ In patients with moderately severe renal function impairment (creatinine clearances 10–30 mL/min/1.73 cubic meters of body surface area).### Several studies reported terminal elimination half-life values of 50 to 60 hours. However, these lower ``accumulation"" half-life values are recommended for use in clinical practice, e.g., for estimating time to reach steady-state, determining appropriate dosing intervals, and determining intervals for dosage adjustment.**** In geriatric patients.†††† Average; usual range 30 to 60 hours, but values ranging from 14 to 158 hours have been reported. Half-life may be especially prolonged in patients with renal function impairment.Physicochemical characteristics:

Note: 6-MNA, the active metabolite of nabumetone, but not nabumetone itself, is acidic. Other NSAIDs not listed above are also acidic.

Mechanism of action/Effect:

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme cyclo-oxygenase, resulting in decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Also, meclofenamate and mefenamic acid have been shown to inhibit competitively the actions of prostaglandins. Although the resultant decrease in prostaglandin synthesis and activity in various tissues may be responsible for many of the therapeutic (and adverse) effects of NSAIDs, other actions may also contribute significantly to the therapeutic effects of these medications.

Antirheumatic (nonsteroidal anti-inflammatory):

Act via analgesic and anti-inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. These medications do not affect the progressive course of rheumatoid arthritis.

Analgesic:

May block pain impulse generation via a peripheral action that may involve reduction of the activity of prostaglandins, and possibly inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation. The antibradykinin activity of ketoprofen may also be involved in relief of pain, because bradykinin has been shown to act together with prostaglandins to cause pain. {216}2

Antigout agent:

Act via analgesic and anti-inflammatory mechanisms; do not correct hyperuricemia.

Anti-inflammatory (nonsteroidal):

Exact mechanisms have not been determined. NSAIDs may act peripherally in inflamed tissue, probably by reducing prostaglandin activity in these tissues and possibly by inhibiting the synthesis and/or actions of other local mediators of the inflammatory response. Inhibition of leukocyte migration, inhibition of the release and/or actions of lysosomal enzymes, and actions on other cellular and immunological processes in mesenchymal and connective tissue may be involved. Indomethacin has been shown to inhibit phosphodiesterase, with a resultant increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. Ketoprofen has been shown to inhibit leukotriene synthesis, inhibit bradykinin activity, and stabilize lysosomal membranes. {216}1

Antipyretic:

Probably produce antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation, resulting in increased blood flow through the skin, sweating, and heat loss. The central action probably involves reduction of prostaglandin activity in the hypothalamus.

Antidysmenorrheal:

By inhibiting the synthesis and activity of intrauterine prostaglandins (which are thought to be responsible for the pain and other symptoms of primary dysmenorrhea), NSAIDs decrease uterine contractility {216}0 and uterine pressure, {216}9 increase uterine perfusion, and relieve ischemic as well as spasmodic pain. {216}8 The antibradykinin activity of ketoprofen may also be involved in relief of dysmenorrhea, because bradykinin has been shown to induce uterine contractions and to act together with prostaglandins to cause pain. {216}7 Also, NSAIDs may relieve to some extent extrauterine symptoms (such as headache, nausea, and vomiting) that may be associated with excessive prostaglandin production. {216}6

Vascular headache prophylactic and suppressant:

Analgesic actions may be involved in relief of headache. Also, by reducing prostaglandin activity, NSAIDs may directly prevent or relieve certain types of headache thought to be caused by prostaglandin-induced dilation or constriction of cerebral blood vessels.

Prostaglandin synthesis inhibitor, renal:

Inhibition of renal prostaglandin synthesis probably is responsible for indomethacin"s beneficial effect in patients with Bartter"s syndrome, which is thought to be caused by excessive production of renal prostaglandins.

Other actions/effects:

Most of the NSAIDs inhibit platelet aggregation. However, their antiplatelet effect, unlike that of aspirin, is reversible. {216}5 Single doses of 4 to 10 mg of flurbiprofen inhibit platelet aggregation. {216}4{216}3{216}2 Oxaprozin is as potent as aspirin in inhibiting platelet aggregation induced by epinephrine or collagen in vitro . {216}1{216}0{216}9 With diflunisal, the effect is clinically significant only with greater-than-recommended daily doses. {216}8 Also, usual doses of {216}7 diclofenac, {216}6{216}5 meclofenamate, {216}4 mefenamic acid, {216}3 or nabumetone (as determined after administration of 1000 mg per day for 7 to 10 days) {216}2{216}1{216}0{216}9 may not significantly alter platelet aggregability. Recovery of platelet function may occur within 1 day after discontinuation of diclofenac, {216}8{216}7 diflunisal, {216}6 flurbiprofen, {216}5{216}4 ibuprofen, indomethacin, or sulindac; 2 days after discontinuation of tolmetin; 4 days after discontinuation of naproxen; or 2 weeks following discontinuation of slowly eliminated agents such as oxaprozin {216}3 or piroxicam.

Studies have demonstrated that IgM rheumatoid factor production (which may be partially mediated by prostaglandins) may be decreased (but not totally inhibited) during NSAID therapy. {216}7{216}6{216}5 However, because these medications do not affect the progressive course of rheumatoid arthritis, the clinical significance of this effect has not been determined. {216}4

It has been proposed that the gastrointestinal toxicity of NSAIDs may be caused primarily by reduction of the synthesis and activity of prostaglandins (which exert a protective effect on the gastrointestinal mucosa) because upper gastrointestinal toxicity has been reported following rectal or parenteral administration of some of these medications. However, when administered orally, some of these acidic medications probably also exert a direct irritant or erosive effect on the mucosa. {216}3 Because nabumetone is a nonacidic prodrug, {216}2{216}1 and the active metabolite 6-MNA is not formed until after absorption, {216}0{215}9{215}8 the risk of serious upper gastrointestinal tract toxicity may be lower with nabumetone than with other NSAIDs. {215}7{215}6 Also, in one study, gastric and duodenal prostaglandin concentrations were not altered by 4 weeks of administration of therapeutic doses of etodolac. {215}5

The renal toxicity associated with NSAIDs (i.e., decreased renal perfusion, sodium and fluid retention, and decreased renal function) may be caused by inhibition of renal prostaglandins, which are directly involved in the maintenance of renal hemodynamics and sodium and fluid balance. Renal prostaglandins are especially important in maintaining renal function in the presence of generalized vasoconstriction or volume depletion. {215}4{215}3{215}2 Sulindac is a prodrug; its sulfide metabolite is the active substance. Because this active metabolite is not excreted via the kidneys, renal toxicity may be less likely with sulindac than with other NSAIDs. However, there have been reports of renal toxicity associated with sulindac therapy. {215}1 Etodolac has been shown to decrease some measures of renal function, {215}0{161}9 with maximum effects occurring within 1.5 {161}8{161}7 to 2.5 {161}6 hours after a dose. However, with administration of up to 500 mg every 12 hours, recovery of renal function occurred prior to administration of the next dose, even in patients with pre-existing mild to moderate renal function impairment (creatinine clearances ranging from 20 to 88 mL per minute). {161}5{161}4 Whether more frequent administration of etodolac may cause cumulative effects on renal function has not been determined. {161}3

The analgesic, antipyretic, and anti-inflammatory effects of NSAIDs may mask symptoms of the onset and/or progression of an infection. {161}2

Therapeutic effect

When these medications are used in the treatment of arthritis, their analgesic actions may produce some relief of pain within the first day or two. Significant relief of other symptoms of inflammation usually occurs within a few days to a week; however, in severe cases, 2 weeks or more of continuous use may be required. {161}1

Studies with several of the NSAIDs have shown that these medications enter the synovial fluid and that, several hours after administration of a single dose, synovial fluid concentrations equal or exceed the simultaneously measured plasma concentration. {293}4{293}3{293}2{293}1{293}0{216}9{216}8{216}7{216}6{216}5{216}4 In addition, there is some evidence that ketoprofen, oxaprozin, {216}3 and possibly other NSAIDs, may accumulate in synovial fluid when administered chronically.

* Elimination.† Determined at steady-state, after administration of a single dose in patients receiving chronic therapy (for diclofenac—50 mg 3 times a day; for flurbiprofen—100 mg twice a day; for tiaprofenic acid—200 mg 3 times a day for 7 days or 300 mg twice a day for 7 days; for tolmetin—400 mg 4 times a day for 7 days).‡ Determined at steady-state.§ Single dose; simultaneous plasma concentration 36 mcg/mL.# Multiple doses (1000 mg every 12 hours on the first day, then 1000 mg per day for 3 days); simultaneous plasma concentration 41 mcg/mL.

Precautions to ConsiderCross-sensitivity and/or related problems

Patients sensitive to one of the nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ketorolac, and NSAIDs no longer commercially available (such as oxyphenbutazone, suprofen, and zomepirac) may be sensitive to any of the other NSAIDs also.

NSAIDs may cause bronchoconstriction or anaphylaxis in aspirin-sensitive asthmatics, especially those with aspirin-induced nasal polyps, asthma, and other allergic reactions (the “aspirin triad”).

Patients with bronchospastic reactions to aspirin may be desensitized to this effect by administration of initially small and gradually increasing doses of aspirin. Desensitization must be carried out by physicians who are experienced with the technique, in a facility having personnel, equipment, and medications immediately available for treatment of any adverse reaction to the medication (especially anaphylaxis or severe bronchospasm). Desensitization to aspirin also desensitizes the patient to other NSAIDs. However, unless aspirin or another NSAID is then administered on a daily basis, sensitivity to these medications redevelops within a few days. {215}8Carcinogenicity

Diclofenac:

No oncogenic potential was demonstrated with diclofenac sodium in a 2-year carcinogenicity study in male mice given up to 0.3 mg per kg of body weight (mg/kg) (0.9 mg per square meter of body surface area [mg/m 2]) per day or in female mice given up to 1 mg/kg (3 mg/m 2) per day.

Diflunisal:

No effect on the incidence or type of neoplasia was found in a 105-week study in rats {215}7{215}6 given up to 40 mg/kg per day (approximately 1.3 times the maximum recommended human dose [MRHD]) or in long-term studies in mice given up to 80 mg/kg per day (approximately 2.7 times the MRHD). {215}5

Etodolac:

No carcinogenicity was demonstrated in mice or rats receiving up to 15 mg/kg per day (corresponding to 45 mg/m 2 for mice and 89 mg/m 2 for rats) for 2 years or 18 months, respectively. {215}4

Floctafenine:

No effect on the incidence of neoplasia was found in studies in CD-1 mice receiving up to 240 mg/kg per day. {215}3

Flurbiprofen:

No evidence of carcinogenicity was found in an 80-week study in mice receiving up to 14 mg/kg per day or in a 2-year study in rats receiving up to 12 mg/kg per day for 32 weeks, then up to 5 mg/kg per day thereafter. {215}2

Indomethacin:

No evidence of carcinogenicity was found in studies in mice receiving up to 1.5 mg/kg per day for 62 to 88 weeks or in studies in rats receiving up to 1.5 mg/kg per day for 73 to 110 weeks. {215}1{215}0

Leukemia has been reported in a few patients receiving indomethacin; however, a causal relationship has not been established. {161}9

Ketoprofen:

No evidence of carcinogenicity was found in studies in mice receiving up to 32 mg/kg (96 mg/m 2) per day (approximately 0.5 times the MRHD based on body surface area). {161}8

Meclofenamate:

No evidence of carcinogenicity was found in an 18-month study in rats. {161}7{161}6

Meloxicam:

No carcinogenic effect was observed in a 104–week study in rats or in a 99–week study in mice{161}5.

Naproxen:

No evidence of carcinogenicity was found in a 24-month study in rats. {161}4{161}3

Oxaprozin:

An increased incidence of hepatic adenomas and carcinomas occurred in 2-year studies in male CD mice, but not in female CD mice or in rats, given oxaprozin. The significance of this species-specific finding is not known. {161}2

Phenylbutazone:

Leukemia has been reported in a few patients receiving phenylbutazone; however, a causal relationship has not been established.

Long-term studies in animals have not been done to determine whether phenylbutazone has carcinogenic activity. {161}1

Tenoxicam:

No evidence of carcinogenicity was found in an 80-week study in mice receiving up to 5 mg/kg per day or in a 104-week study in rats receiving up to 6 mg/kg per day. {161}0

Tiaprofenic acid:

No evidence of carcinogenicity was found in an 80-week study in mice receiving up to 30 mg/kg per day or in a 104-week study in rats receiving up to 30 mg/kg per day. {161}9{161}8

Tolmetin:

No evidence of carcinogenicity was found in an 18-month study in mice receiving up to 50 mg/kg per day or in a 24-month study in rats receiving up to 75 mg/kg per day. {161}7{161}6

Tumorigenicity

Diclofenac

No tumorigenicity was demonstrated in studies in rats receiving up to 2 mg/kg per day (approximately the recommended human dose). {161}5 Although there was a slight increase in benign mammary fibroadenomas in female rats given 0.5 mg/kg (3 mg/m 2) per day, the increase was not significant. {161}4

Flurbiprofen

No tumorigenicity was demonstrated in a 2-year study in rats receiving up to 12 mg/kg per day for 32 weeks, then up to 5 mg/kg per day. {161}3

Indomethacin

No tumorigenicity was demonstrated in an 81-week study in rats receiving up to 1 mg/kg per day. {161}2{161}1

Ketoprofen

No tumorigenicity was demonstrated in studies in rats receiving 6 mg/kg (36 mg/m 2) per day for 81 weeks or lower doses for 104 weeks. {161}0

Nabumetone

No tumorigenicity was demonstrated in 2-year studies in mice and rats. {215}9

Mutagenicity

Diclofenac:

No mutagenic activity was demonstrated in in vitro tests using mammalian cells or bacteria (with or without microsomal activation) or in in vivo tests, including dominant lethal and male germinal epithelial chromosomal studies in mice and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. {215}8

No mutagenic activity was demonstrated in in vitro tests performed with Salmonella typhimurium and mouse lymphoma cells or in an in vivo mouse micronucleus test. However, in the in vitro human peripheral lymphocyte test, concentrations of 50 to 200 mcg per mL (mcg/mL) of etodolac produced an increase in the number of gaps (3 to 5.3% unstained regions in the chromatid without dislocation, compared with 2% in controls). {215}6

Indomethacin:

No mutagenic activity was demonstrated in in vitro tests (Ames test or E. coli , with or without metabolic activation) or in in vivo tests (host-mediated assay, sex-linked recessive lethals in Drosophila , and micronucleus test in mice). {215}5{215}4

No mutagenic activity was demonstrated in the Ames test or in the mouse micronucleus test in vivo . However, chromosomal aberrations occurred in lymphocytes exposed in vitro to nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA) at concentrations of 80 mcg/mL (369.6 micromoles/L) or higher. {215}1

No mutagenic activity was demonstrated in tests in mice, Chinese hamsters, or rats given up to 33 times the maximum daily human dose, or in bacteria or fungi. However, in vitro tests using Chinese hamster fibroblast cells have shown that phenylbutazone concentrations exceeding 860 mg/L produce chromosome abnormalities. Although an increased incidence of chromosome anomalies has been reported in cultured leukocyte cells from patients receiving therapeutic doses of the medication, other similar studies in humans and in horses have yielded inconclusive or negative results. {216}9

Piroxicam:

No mutagenic activity was demonstrated (test systems used not specified). {216}8

No impairment of fertility was demonstrated in reproduction studies in rats receiving up to 4 mg/kg (24 mg/m 2) per day. {216}2

Diflunisal

No impairment of fertility was demonstrated in reproduction studies in rats receiving up to 50 mg/kg per day. {216}1{216}0

Etodolac

A reduction in the implantation of fertilized eggs was demonstrated in reproduction studies in rats receiving 8 mg/kg per day, but no impairment of fertility was demonstrated in male or female rats receiving up to 16 mg/kg (94 mg/m 2) per day. {216}9

Floctafenine

No impairment of fertility was demonstrated in reproduction studies in rats receiving up to 160 mg/kg per day. {216}8

Flurbiprofen

No impairment of fertility was demonstrated in reproduction studies in rats receiving 2.25 mg/kg per day. {216}7{216}6

Indomethacin

No impairment of fertility was demonstrated in a 2-generation reproduction study in mice or in a 2-litter reproduction study in rats receiving up to 0.5 mg/kg per day. {216}5{216}4

Ketoprofen

No impairment of fertility was demonstrated in reproduction studies in male rats receiving up to 9 mg/kg (54 mg/m 2) per day. However, a decrease in the number of implantation sites was demonstrated in female rats receiving 6 or 9 mg/kg (36 or 54 mg/m 2) per day. In other studies, high doses of ketoprofen caused abnormal spermatogenesis or inhibition of spermatogenesis in rats and dogs, and decreased testicular weight in dogs and baboons. {216}3

Mefenamic acid

Impairment of fertility was demonstrated in reproduction studies in rats receiving 10 times the human dose. {216}2{216}1

Meloxicam

No impairment of fertility was demonstrated in male or female rats receiving 4.9 times the human dose {216}0.

Nabumetone

No impairment of fertility was demonstrated in male or female rats receiving 320 mg/kg (1888 mg/m 2) per day. {211}

Naproxen

No impairment of fertility was demonstrated in mice, rats, or rabbits receiving up to 6 times the human dose. {01}{188}

Oxaprozin

No impairment of fertility was demonstrated in male or female rats receiving up to 200 mg/kg (1180 mg per square meter of body surface area [mg/m 2]) per day. For comparison, the usual human dose is about 17 mg/kg (629 mg/m 2) per day. However, testicular degeneration occurred in beagle dogs given 37.5 mg/kg (750 mg/m 2) or more per day for 42 days or longer. This finding did not occur in other species, and the clinical relevance to humans is unknown. {163}

Phenylbutazone

No impairment of fertility was demonstrated in reproduction studies in mice, Chinese hamsters, and rats receiving up to 33 times the maximum daily human dose. {42}

Piroxicam and tolmetin

No impairment of fertility was demonstrated in animal reproduction studies. {44}{49}{215}

Tenoxicam

No impairment of fertility was demonstrated in male rats receiving up to 8 mg per day for at least 63 days prior to mating. Administration of 8 mg per day, but not lower doses, to female rats from 14 days prior to, to 7 days after, mating resulted in a significant decrease in the number of corpora lutea and implantations, resulting in fewer live fetuses. {180}

Tiaprofenic

No impairment of fertility was demonstrated in reproduction studies in female or {132} male rats receiving up to 20 mg/kg per day. However, an increased number of pre- and post-implantation losses was demonstrated in studies in female rats receiving 20 mg/kg per day, and a decrease in the number of implantation sites was demonstrated in studies in rabbits receiving 75 mg/kg per day. {48}{213}

Pregnancy—

First trimester

Diclofenac—

Adequate and well-controlled studies in humans have not been done.

Diclofenac crosses the placenta in mice and rats. {158} Studies in rats receiving 2 or 4 mg/kg per day have shown that diclofenac is embryotoxic (causing low birth weight, a slightly decreased growth rate, and failure to survive, especially with the higher dose). Also, in studies in rabbits receiving 5 or 10 mg/kg per day, diclofenac caused increases in the resorption rates, decreased fetal weights, abnormal skeletal findings, and definite embryotoxicity with the higher dose. {218} However, no teratogenicity was demonstrated in reproduction studies in rabbits receiving up to 10 mg/kg (80 mg/m 2) per day, in mice receiving up to 20 mg/kg (60 mg/m 2) per day, or in rats receiving up to 10 mg/kg (60 mg/m 2) per day. {158}

Studies in animals have shown that diflunisal is teratogenic in rabbits (causing fetal vertebral and rib malformations at doses ranging from 40 to 50 mg/kg per day) but not in mice (in doses of 45 mg/kg per day) or rats (in doses of 100 mg/kg per day). Diflunisal also caused maternotoxicity and embryotoxicity (increased fetal resorptions) in rabbits receiving 60 mg/kg per day (2 times the maximum human dose).

Isolated alterations of limb development, including polydactyly (extra digits), oligodactyly (missing digits), syndactyly (digits attached by webbing), and unossified phalanges, occurred in rats receiving 2 to 14 mg/kg per day. Also, oligodactyly and synostosis of metatarsals occurred in rabbits receiving 2 to 14 mg/kg per day. However, the frequency and dosage group distribution in initial and repeated studies did not establish a clear drug- or dose-response relationship.

Studies in animals have not shown that these agents cause adverse effects on fetal development. Naproxen was studied in mice, rats, and rabbits receiving up to 6 times the human dose. Tolmetin was studied in rats and rabbits receiving up to 50 mg/kg (1.5 times the maximum human dose). {181}{186}{188}{215}

Naproxen: FDA Pregnancy Category B.

Tolmetin: FDA Pregnancy Category C.

Floctafenine—

Studies in mice receiving up to 320 mg/kg per day, rats receiving up to 240 mg/kg per day, and rabbits receiving up to 160 mg/kg per day have not shown that floctafenine is teratogenic. However, embryotoxicity (increased fetal losses in mice, decreased fetal weight in rats, and increased fetal losses in rabbits) was demonstrated with these high doses (but not at lower dosage levels). {28}

Flurbiprofen—

Although adequate and well-controlled studies in humans have not been done, it has been shown that flurbiprofen crosses the placenta.

Studies in mice receiving up to 12 mg/kg per day, rats receiving up to 25 mg/kg per day, and rabbits receiving up to 7.5 mg/kg per day have not shown evidence of teratogenicity. {144} However, studies in rats have shown doses of 0.4 mg/kg per day or higher to be embryocidal (causing reduced weight or slower fetal growth, increased stillbirths, and decreased pup survival). Also, stillbirths, retained fetuses, and/or fetal distress occurred in studies in rats receiving as little as 0.2 mg/kg per day. In addition, fetotoxicity related to maternal toxicity (gastrointestinal ulceration, retardation of weight gain, intrauterine hemorrhage, and maternal deaths) occurred in rats receiving 25 mg/kg per day from Days 1 through 20 of pregnancy. With lower doses (0.2, 0.675, or 2.25 mg/kg per day), such effects did not occur when the medication was discontinued on Day 17 of pregnancy. Maternal deaths due to gastrointestinal ulceration also occurred in rabbits receiving the medication. {29}{30}{221}

Although studies in humans have not been done, it has been shown that indomethacin crosses the placenta. {08}

Studies in rats and mice have shown that indomethacin (at a dosage of 4 mg/kg per day) causes decreased average fetal weight and retarded ossification. In other studies in mice, higher doses (5 to 15 mg/kg per day) caused maternal toxicity and death, increased fetal resorptions, and fetal malformations. {176}

Ketoprofen—

Adequate and well-controlled studies in humans have not been done.

Studies in animals have not shown evidence of teratogenicity or embryotoxicity in mice receiving up to 12 mg/kg (36 mg/m 2) per day or in rats receiving up to 9 mg/kg (54 mg/m 2) per day. In studies in rabbits, maternally toxic doses were embryotoxic but not teratogenic.

Although adequate and well-controlled studies in humans have not been done, it has been demonstrated that mefenamic acid metabolites readily cross the placenta.

Mefenamic acid caused increases in the number of resorptions in rabbits receiving 2.5 times the human dose and decreases in survival to weaning (possibly due to maternal neglect) in rats receiving 10 times the human dose. Although no fetal abnormalities were reported in these studies or in studies in dogs receiving up to 10 times the human dose, it has been recommended that mefenamic acid not be used during pregnancy.

Adequate and well-controlled studies in humans have not been done{320}.

Meloxicam crosses the placenta in animals.

Meloxicam was not teratogenic in rats at a dose equivalent to 2.2 times the human dose when given throughout organogenesis. However, an increased incidence of embryolethality occurred when female rats were given half the human dose 2 weeks before mating and during early embryonic development. The number of live births and neonatal survival were reduced in rats give oral doses equivalent to 0.07 times the human dose during late gestation and lactation periods{320}

Nabumetone—

Adequate and well-controlled studies in humans have not been done.

Nabumetone did not cause teratogenicity in rats receiving up to 400 mg/kg (2360 mg/m 2) per day or in rabbits receiving up to 300 mg/kg (3540 mg/m 2) per day. However, fetotoxicity (post-implantation losses) occurred in rats receiving 100 mg/kg (590 mg/m 2) per day or more. These doses are equivalent to the maximum recommended human dose of nabumetone.

Adequate and well-controlled studies in humans have not been done. {163}

Fetal malformations occurred infrequently in rabbits receiving 7.5 to 30 mg/kg per day (doses within the usual human dose range). However, no teratogenicity occurred in mice or rats receiving 50 to 200 mg/kg (225 to 900 mg/m 2) per day.

Although studies in rats and rabbits have not shown that phenylbutazone (in doses up to 16 times the maximum daily human dose) is teratogenic, slightly reduced litter sizes were demonstrated in both species.

FDA Pregnancy Category C.

Piroxicam—

Studies in humans have not been done.

Studies in animals have not shown that piroxicam causes teratogenic effects in doses up to 10 mg/kg per day. {167}

Sulindac—

Studies in humans have not been done.

Animal studies have shown that sulindac (at dosage levels of 20 and 40 mg/kg per day—2.5 and 5 times the MRHD) causes decreased average fetal weight and an increased number of deaths (observed on the first day of the postpartum period). Also, some studies in rabbits have shown a low incidence of visceral and skeletal malformations with sulindac. However, these effects did not occur in repeat studies using the same or higher dosages. {46}{223}

Tenoxicam—

Studies in mice receiving up to 8 mg/kg per day from Day 6 to Day 15 of gestation did not show tenoxicam to adversely affect the fetuses or neonates. Teratogenic effects did not occur in offspring of rats receiving up to 12 mg/kg per day from Day 7 to Day 17 of gestation. However, a higher mortality rate associated with panperitonitis, gastric lesions characteristic of NSAIDs, and uterine hemorrhage occurred in dams receiving 8 or 12 mg/kg, but not 4 mg/kg or less, per day. Tenoxicam was embryotoxic (causing increased resorptions), but not teratogenic, in rabbits receiving 32 mg/kg, but not 16 mg/kg or less, per day from Day 6 to Day 18 of gestation. {180}

Tiaprofenic acid—

Tiaprofenic acid crosses the placenta.

Studies in mice receiving up to 100 mg/kg per day have not shown that the medication is teratogenic. However, an increase in the fetal loss rate was demonstrated in studies in mice receiving 100 mg/kg per day, rats receiving 10 or 25 (but not 5) mg/kg per day, and rabbits receiving 75 (but not 25 or 50) mg/kg per day. {48}{213}

Second and third trimesters

All NSAIDs—

Although studies in humans have not been done with NSAIDs other than indomethacin, use of NSAIDs during the second half of pregnancy is not recommended because of possible adverse effects on the fetus, such as premature closure of the ductus arteriosus, which may lead to persistent pulmonary hypertension in the newborn. Studies in full-term pregnant rats have shown that diclofenac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, and tolmetin have a strong constrictive effect on the fetal ductus arteriosus, whereas floctafenine, phenylbutazone, piroxicam, sulindac, and tiaprofenic acid have a moderate constrictive effect. {16}

Animal studies have also shown that administration of NSAIDs during late pregnancy may cause prolonged gestation, dystocia, and delayed parturition, possibly because of decreased uterine contractility resulting from inhibition of uterine prostaglandins. Decreases in pup survival rates also have been reported. Studies with piroxicam {45} and nabumetone (at a dose of 320 mg/kg per day) {211} have indicated that dystocia may cause an increased mortality rate in both offspring and dams, {45} and a study with tenoxicam showed a dose-dependent prolongation of gestation and decrease in neonatal viability with doses ranging between 0.5 and 2 mg/kg per day. {180} Also, delayed and prolonged parturition was associated with decreased pup survival in studies with etodolac {177} and with an increased number of stillbirths in studies with flurbiprofen {29} and tiaprofenic acid. {48} Administration of indomethacin to rats and mice during the last 3 days of gestation increased the incidence of neuronal necrosis in the diencephalon and caused maternal and fetal deaths. {176} Administration of oxaprozin to rats during late pregnancy resulted in decreased pup survival, {163} and administration of 3.5 times the maximum human daily dose of phenylbutazone to rats during late pregnancy and lactation resulted in an increased number of stillbirths and reduced survival of offspring. Studies in animals have also shown that administration of piroxicam during the third trimester may increase the risk of maternal gastrointestinal tract toxicity. {167}

Indomethacin—

In addition to the adverse effects in animal studies described above, administration of indomethacin to pregnant women during the third trimester has caused closure of the ductus arteriosus, inhibition of platelet function resulting in bleeding, renal function impairment or failure with oligohydramnios, gastrointestinal bleeding or perforation, and myocardial degenerative changes in the fetus. {176}

Breast-feeding

Problems in humans have not been documented with most of the NSAIDs.

Diclofenac:

Diclofenac is distributed into breast milk. In one study, long-term use of 150 mg per day produced concentrations of 100 nanograms per gram in the breast milk. {158} An infant of 4 to 5 kg consuming one liter per day would therefore ingest approximately 0.03 mg/kg per day. {23}

Diflunisal:

Diflunisal is distributed into breast milk. Concentrations may reach 2 to 7% of the maternal plasma concentration. {24}{219}

Fenoprofen and mefenamic acid are distributed into breast milk in very small quantities. {26}{38}{209}

Flurbiprofen:

Flurbiprofen is distributed into breast milk in very small quantities. In one study, the peak concentration of 0.09 mcg/mL occurred 3 hours following a single 100-mg dose. A maximum of 0.07% of the dose appeared in breast milk within 24 hours after administration. {81} A nursing infant whose mother is taking 200 mg per day could receive approximately 0.1 mg of flurbiprofen per day. {144}

Ibuprofen:

Studies in humans have failed to detect ibuprofen in breast milk using methodology capable of detecting the medication in a concentration of 1 mcg/mL. The maternal dosage was 400 mg four times a day. {17}{31}{181}{182}{222}

Indomethacin:

Indomethacin is distributed into breast milk. {175}{176} Risk-benefit must be considered because convulsions were reported in one breast-fed infant whose mother received 200 mg of indomethacin per day, of which 0.5 to 2 mg per day was distributed into the breast milk.

Ketoprofen:

It is not known whether ketoprofen is distributed into human breast milk; however, in animal studies, the concentration in the milk of lactating dogs was 4 to 5% of the maternal plasma concentration. In other studies, no adverse effect on perinatal development was observed in offspring of rats receiving 9 mg/kg (54 mg/m 2) per day, corresponding to 1.5 times the MRHD based on weight or 0.3 times the MRHD based on body surface area. {205}

Meclofenamate:

Trace amounts of meclofenamate are distributed into breast milk. Use of meclofenamate in nursing mothers is not recommended because animal studies have shown meclofenamate to interfere with normal development of the young before weaning. {178}

Meloxicam:

Studies of distribution of meloxicam into human breast milk have not been done{320}. However, meloxicam has been found in the milk of lactating rats at concentrations higher than those in plasma{320}.

Nabumetone:

It is not known whether nabumetone or its metabolites are distributed into human breast milk. {211} Problems in humans have not been documented. However, 6-MNA is distributed into the milk of lactating rats {211}{250} in concentrations approximately equal to those in plasma. {250}

Naproxen:

Naproxen is distributed into breast milk; concentrations may reach 1% of the maternal plasma concentration. {01}{198} The peak concentration in breast milk occurs 4 hours after a dose. {18}

Oxaprozin:

It is not known whether oxaprozin is distributed into human breast milk. However, it is distributed into the milk of lactating rats. {163}

Phenylbutazone:

Phenylbutazone is distributed into breast milk; {224} use by nursing mothers may cause severe adverse effects, including blood dyscrasias, in the infant.

Piroxicam:

Piroxicam is distributed into breast milk; concentrations may reach 1 to 3% of the maternal plasma concentration. {168} Also, use of piroxicam by nursing mothers is not recommended because studies in rats have shown that piroxicam causes a dose-dependent inhibition of lactation. {45}{168}

Sulindac:

It is not known whether sulindac is distributed into human breast milk, but it is distributed into the milk of lactating rats. {46}{223}

Tolmetin:

Tolmetin is distributed into breast milk. {20}{215} In one study, an average concentration of 0.075 mcg/mL was measured, with the peak concentration occurring 1 hour following administration to the mother. The half-life in breast milk was 1.5 hours. {20}

Pediatrics

Ibuprofen:

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of ibuprofen in children 6 months of age or older. {139}{183} Safety and efficacy in infants younger than 6 months of age have not been established. {139}{183}

Indomethacin:

Although appropriate studies have not been done in the pediatric population, no pediatrics-specific problems have been documented to date (with the immediate-release capsule or oral suspension dosage form; the extended-release dosage form is not recommended for pediatric patients). {130}{176} However, because of indomethacin's toxicity, it is recommended that its use be limited to patients unresponsive to (or intolerant of) other antirheumatic agents, {32}{176} that the patient be carefully monitored (especially for the presence of infection), and that the recommended pediatric doses not be exceeded. {32}

Naproxen:

Studies in children 2 years of age and older with juvenile arthritis have shown higher incidences of naproxen-induced skin rash and increased bleeding time as compared with adults. Studies in children younger than 2 years of age have not been done. {01}{188}

Oxaprozin:

Although a study with oxaprozin has been conducted in patients 3 to 16 years of age, {269} controlled studies have not been published. Preliminary evidence indicates that, although the risk of overt hepatotoxicity appears to be minimal, elevated aspartate aminotransferase (AST [SGOT]) values during oxaprozin therapy may occur more often in patients treated for juvenile arthritis than in patients treated for other forms of arthritic disease. {287} Safety and efficacy in pediatric patients have not been established. {163}

Phenylbutazone:

Because of phenylbutazone's toxicity, use in children younger than 15 years of age is not recommended. {224}

Tolmetin:

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of tolmetin in children 2 years of age or older. Studies in children younger than 2 years of age have not been done. {49}{215}

Whether geriatric patients are at increased risk of serious gastrointestinal toxicity during NSAID therapy has not been established. However, NSAID-induced gastrointestinal ulceration and/or bleeding may be more likely to cause serious consequences, including fatalities, in geriatric patients than in younger adults. {144}{158}{159}{164}{167}{176}{178}{181}{186}{215} In addition, elderly patients are more likely to have age-related renal function impairment, which may increase the risk of NSAID-induced hepatic or renal toxicity and may also require dosage reduction to prevent accumulation of the medication. Some clinicians recommend that geriatric patients, especially those 70 years of age or older, be given one half of the usual adult dose initially. Also, careful monitoring of the patient is recommended. {294}

Etodolac:

Studies performed to date with 200 mg of etodolac twice a day {230}{231} have not shown differences in the pharmacokinetics of the medication in geriatric patients compared with younger adults. {177}{230}{231} Also, studies with 600 mg of etodolac per day {265} have not shown differences in the side effects profile of etodolac in geriatric patients compared with younger adults. {177}{265}

Flurbiprofen:

Studies have shown that the peak plasma concentration of flurbiprofen may be increased in females 74 to 94 years of age, but not in males 66 to 90 years of age.

Indomethacin:

In addition to the increased risks of therapy with any NSAID as described above, geriatric patients are more likely to develop adverse CNS effects, especially confusion, while taking indomethacin.

Ketoprofen:

Studies have shown that protein binding and clearance of ketoprofen may be reduced, leading to increased and prolonged serum concentration and elimination half-life. {35}

Nabumetone:

Studies in geriatric patients have not shown differences in the efficacy or safety of nabumetone compared with younger adults. {210}{211}{274} However, plasma concentrations of 6-MNA are higher in geriatric patients, and interpatient variability in the pharmacokinetic parameters for 6-MNA is greater in geriatric patients than in younger adults. {275}{276}

Naproxen:

Studies have shown that the unbound (free) fraction of naproxen, but not the total plasma concentration, may be increased in geriatric patients. {01}{75}{188} The steady-state concentration of unbound naproxen may be almost doubled in geriatric patients as compared with younger adults. {75}

Oxaprozin:

Studies have not demonstrated a need for adjustment of initial oxaprozin dosage in elderly patients on the basis of pharmacokinetic considerations. {163}

The relationship of age to the risk of adverse effects in patients receiving oxaprozin has been examined using data from 3 studies in patients with rheumatoid arthritis and 1 study in patients with osteoarthritis. The data indicate that oxaprozin is more likely to cause a potentially significant decrease in renal function, adverse gastrointestinal effects, or a significant decrease in hemoglobin concentration in patients older than 60 years of age than in younger adults. {288} Although it has also been reported, with other NSAIDs, that geriatric patients seem to be more susceptible to NSAID-induced hepatotoxicity, {289} there were no significant age-related differences in measures of hepatic function in the 4 studies with oxaprozin. {288}

Phenylbutazone:

In patients 60 years of age and over, therapy should be limited to short periods (not to exceed 1 week if possible) because of the high risk of severe, possibly fatal, toxic reactions. Specifically, the risk of aplastic anemia and agranulocytosis is increased in elderly patients. {42}

The risk of adverse renal effects reflected by hyperkalemia and/or an increase in blood urea nitrogen (BUN) may be increased in elderly patients; an increase in BUN occurred in 11.8% of elderly patients, but only 2.5% of all patients, in clinical trials. {213}

Dental

NSAIDs may cause soreness, irritation, or ulceration of the oral mucosa.

Most of the NSAIDs may rarely cause leukopenia and/or thrombocytopenia, which may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. {123}Surgical

Caution is recommended in patients who require surgery. Most NSAIDs inhibit platelet aggregation and may prolong bleeding time, which may increase intra- and postoperative bleeding. The risk may be lower with usual doses of diclofenac, {158}{218} diflunisal, {24} meclofenamate, {37} mefenamic acid, {38} or nabumetone, {210}{250}{251}{252} which may not significantly alter platelet aggregability (although mefenamic acid–induced hypoprothrombinemia, if present, could be hazardous to the patient). Recovery of platelet function may occur within 1 day after discontinuation of diclofenac, {13}{57} diflunisal, {13} flurbiprofen, {51}{61} ibuprofen, indomethacin, or sulindac; 2 days after discontinuation of tolmetin; 4 days after discontinuation of naproxen; or 2 weeks following discontinuation of slowly eliminated agents such as oxaprozin {257} or piroxicam. Consideration should be given to discontinuing NSAID treatment for an appropriate length of time prior to elective surgery, depending on the potency and duration of effect of the individual agent on platelet aggregability. In particular, it is recommended that treatment with oxaprozin, which is as potent as aspirin in inhibiting platelet aggregation, {255}{256}{257} be discontinued 1 to 2 weeks prior to elective surgery. {290}Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
In addition to the interactions listed below, the possibility should be considered that additive or multiple effects leading to impaired blood clotting and/or increased risk of bleeding may occur if any NSAID is used concurrently with any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.

For all NSAIDs

Note: All of the following interactions have not been documented with every NSAID. However, they have been reported with several of these medications and should be considered potential precautions to the use of any NSAID, especially with chronic administration. {309}

Acetaminophen (prolonged concurrent use of acetaminophen with an NSAID may increase the risk of adverse renal effects; it is recommended that patients be under close medical supervision while receiving such combined therapy)

(concurrent use with diflunisal may also increase the risk of acetaminophen-induced hepatotoxicity because diflunisal may increase the acetaminophen plasma concentration by 50%)

Alcohol or
Corticosteroids, glucocorticoid or
Corticotropin (chronic therapeutic use) or
Potassium supplements (concurrent use with an NSAID may increase the risk of gastrointestinal side effects, including ulceration or hemorrhage; however, concurrent use with a glucocorticoid or corticotropin in the treatment of arthritis may provide additional therapeutic benefit and permit reduction of glucocorticoid or corticotropin dosage)

» Anticoagulants, coumarin- or indanedione-derivative or» Heparin or» Thrombolytic agents, such as:
Alteplase
Anistreplase
Streptokinase
Urokinase (inhibition of platelet aggregation by NSAIDs, and the possibility of NSAID-induced gastrointestinal ulceration or bleeding, may be hazardous to patients receiving anticoagulant or thrombolytic therapy{320}; although nabumetone may be less likely than other NSAIDs to increase the risk of bleeding because it may be less likely to cause gastrointestinal ulceration or hemorrhage {250}{260} and because it has minimal, if any, platelet aggregation–inhibiting activity, {210}{250}{251}{252} caution is recommended; {210} also, with usual doses, diclofenac, {158}{218} diflunisal, {24} meclofenamate, {37} and mefenamic acid may be less likely than other NSAIDs to significantly alter platelet aggregability)

(diflunisal, etodolac, fenoprofen, floctafenine, flurbiprofen, indomethacin, meclofenamate, mefenamic acid, phenylbutazone, piroxicam, sulindac, tiaprofenic acid, and tolmetin have been reported to potentiate the effects of coumarin- or indanedione-derivative anticoagulants; the effect of floctafenine on coagulation test results becomes apparent only after 2 weeks of concurrent use; potentiation may result from displacement of the anticoagulant from protein-binding sites and, with phenylbutazone, from inhibition of the metabolism of the anticoagulant; concurrent use of phenylbutazone with an anticoagulant is not recommended; if another NSAID is used concurrently, coagulation tests should be monitored and anticoagulant dosage adjustments made, if necessary, when NSAID therapy is initiated or discontinued)

Antidiabetic agents, oral or
Insulin (NSAIDs may increase the hypoglycemic effect of these medications because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism and possibly because of displacement of the oral antidiabetics from serum proteins; dosage adjustments of the antidiabetic agent may be necessary; glipizide and glyburide, due to their nonionic binding characteristics, may not be affected as much as the other oral antidiabetic agents; however, caution with concurrent use is recommended)

(diclofenac has also been reported to decrease the effects of these medications, leading to hyperglycemia)

Antihypertensives or
Diuretics, especially» Triamterene (increased monitoring of the response to an antihypertensive agent may be advisable when any NSAID is used concurrently because flurbiprofen, {144} indomethacin, ibuprofen, naproxen, oxaprozin, and piroxicam have been shown to reduce or reverse the effects of antihypertensives, possibly by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention)

(NSAIDs may decrease the diuretic, natriuretic, and antihypertensive effects of diuretics, probably by inhibiting renal prostaglandin synthesis; flurbiprofen has also been shown to interfere with furosemide-induced kaliuresis {144}; however, diflunisal does not decrease the diuretic effect of furosemide {219})

(indomethacin may block the increase in plasma renin activity [PRA] induced by bumetanide, furosemide, or indapamide)

(concurrent use of an NSAID and a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis; specifically, concurrent use of triamterene and indomethacin is not recommended because this combination has caused renal function impairment [azotemia and reduced creatinine clearance] and a few cases of renal failure requiring hemodialysis)

(concurrent use of a potassium-sparing diuretic with indomethacin or diclofenac, {156}{218} and possibly other NSAIDs, {180}{213} may increase the risk of hyperkalemia)

(diflunisal significantly increases the plasma concentration of hydrochlorothiazide and decreases the hyperuricemic effect of hydrochlorothiazide or furosemide )

» Aspirin or
NSAIDs, two or more concurrently, especially» Diflunisal and indomethacin concurrently {175}{176}{219}{320} or
Salicylates other than aspirin and diflunisal (concurrent use of two or more NSAIDs, including aspirin, is not recommended; concurrent therapy may increase the risk of gastrointestinal toxicity, including ulceration or hemorrhage, without providing additional symptomatic relief; specifically, concurrent use of diflunisal and indomethacin has resulted in fatal gastrointestinal hemorrhage)

(concurrent use of aspirin with other NSAIDs may also increase the risk of bleeding at sites other than the gastrointestinal tract because of additive inhibition of platelet aggregation)

(concurrent administration of two or more NSAIDs may alter the pharmacokinetic profile of at least one of the medications, which may alter the therapeutic effect and/or increase the risk of adverse effects; specifically, aspirin decreases protein binding of ketoprofen {205} and etodolac [but does not alter etodolac clearance], {177} increases plasma clearance of ketoprofen, {205} interferes with the formation and excretion of ketoprofen conjugates, decreases concentrations of the active sulfide metabolite of sulindac, {223} and decreases the bioavailability of diclofenac, {158}{218} diflunisal {219}, fenoprofen, {186} flurbiprofen [by 50%], {144} ibuprofen [by 50% in multiple-dose studies], {182} indomethacin [by 20%], {175}{176} meclofenamate, {178} piroxicam [by 20%], {167} a single dose of tenoxicam [by 20%], {180} and tolmetin. {216} Also, diflunisal decreases the renal clearance of indomethacin, resulting in significantly increased indomethacin plasma concentrations, {175}{176}{219} and decreases the concentration of the active sulfide metabolite of sulindac by 33%. {219}{223} Although studies to determine whether phenylbutazone alters etodolac clearance have not been done, phenylbutazone has been shown in vitro to decrease the protein binding of etodolac, leading to an 80% increase in the concentration of unbound etodolac {177})

Bone marrow depressants (See Appendix II ) (leukopenic and/or thrombocytopenic effects of these medications may be increased with concurrent or recent therapy if an NSAID causes the same effects; dosage adjustment of the bone marrow depressant, if necessary, should be based on blood counts)

Colchicine (concurrent use with an NSAID may increase the risk of gastrointestinal ulceration or hemorrhage, and concurrent use with phenylbutazone may also increase the risk of adverse hematologic effects)

(inhibition of platelet aggregation by NSAIDs, added to colchicine's effects on blood clotting mechanisms [colchicine may cause thrombocytopenia with chronic use and clotting defects, including disseminated intravascular coagulation, with overdose], may increase the risk of bleeding at sites other than the gastrointestinal tract)

» Cyclosporine {158}{176}{177}{218}{219}{223} or
Gold compounds or
Nephrotoxic medications, other (See Appendix II ) (inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of cyclosporine and/or the risk of cyclosporine-induced nephrotoxicity; patients should be carefully monitored during concurrent use)

(the risk of adverse renal effects may also be increased when an NSAID is used concurrently with other nephrotoxic medications, possibly including gold compounds [although NSAIDs and gold compounds are commonly used concurrently in the treatment of arthritis])

Digitalis glycosides (diclofenac and ibuprofen have been shown to increase serum digoxin concentrations, and indomethacin has increased digitalis concentrations in neonates being treated for patent ductus arteriosus; the possibility should be considered that some of the other NSAIDs may also increase digoxin concentrations, {177}{211} leading to an increased risk of digitalis toxicity; increased monitoring and dosage adjustments of the digitalis glycoside may be necessary during and following concurrent NSAID therapy; however, studies have failed to show that flurbiprofen, {144} ketoprofen, {205} piroxicam, {168} or tenoxicam {180} increases digoxin concentrations, and phenylbutazone may decrease digitalis concentrations [see individual For phenylbutazone listing, below] )

» Lithium (diclofenac, ibuprofen, {182}indomethacin, meloxicam{320} naproxen, and piroxicam have been reported to increase the steady-state concentration of lithium, possibly by decreasing its renal clearance; with indomethacin, the steady-state lithium concentration was increased by up to 50%; other NSAIDs may have a similar effect; increased monitoring of lithium concentrations is recommended during and following concurrent use)

» Methotrexate (concurrent use with phenylbutazone may increase the risk of agranulocytosis or bone marrow depression and is not recommended)

(NSAIDs may decrease protein binding and/or renal elimination of methotrexate, resulting in increased and prolonged methotrexate plasma concentrations and an increased risk of toxicity, especially during high-dose methotrexate infusion therapy; indomethacin has caused toxicity with intermediate-dose methotrexate infusions; fatalities have been reported; it is recommended that NSAID therapy be withheld for varying periods of time, depending on the elimination half-life of the individual NSAID [12 to 24 hours for agents with a short elimination half-life to up to 10 or 12 days for agents with a very long elimination half-life] prior to administration of a high-dose methotrexate infusion [for indomethacin, an intermediate- or high-dose methotrexate infusion]; also, NSAID therapy should not be resumed following the infusion until the methotrexate plasma concentration has decreased to a nontoxic level, usually at least 12 hours )

(severe, sometimes fatal, methotrexate toxicity has also been reported when NSAIDs were used concurrently with low to moderate doses of methotrexate, including doses commonly used in the treatment of rheumatoid arthritis or psoriasis; {87}{88}{89} caution in concurrent use is recommended, with dosage of methotrexate being adjusted as determined by monitoring the plasma methotrexate concentration and/or adequacy of the patient's renal function)

Photosensitizing medications, other (concurrent use with photosensitizing NSAIDs may cause additive photosensitizing effects)

Platelet aggregation inhibitors, other (See Appendix II ) (concurrent use with an NSAID may increase the risk of bleeding because of additive inhibition of platelet aggregation, as well as the potential for NSAID-induced gastrointestinal ulceration or hemorrhage)

(concurrent use of sulfinpyrazone with NSAIDs may also increase the risk of gastrointestinal ulceration or hemorrhage)

» Probenecid (concurrent use of probenecid with ketoprofen is not recommended; probenecid decreases ketoprofen's renal clearance [by approximately 66%] and protein binding [by 28%], and inhibits formation and renal clearance of ketoprofen conjugates, leading to greatly increased ketoprofen plasma concentration and risk of toxicity {205})

(probenecid has also been shown to decrease renal and biliary clearance of indomethacin, and to increase plasma concentrations of indomethacin and naproxen, leading to increased risk of toxicity and possibly to increased effectiveness of the NSAID; if concurrent use is necessary, it is recommended that these NSAIDs be administered in reduced dosage and that increases in dosage be made slowly and in small increments {01}{32}{176})

(probenecid may also decrease excretion and increase serum concentrations of other NSAIDs, possibly enhancing effectiveness and/or increasing the potential for toxicity; a decrease in dosage of the NSAID may be necessary if adverse effects occur)

(probenecid may increase the plasma concentration of sulindac and its sulfone metabolite, and slightly decrease the plasma concentration of the active sulfide metabolite {223})

For diflunisal (in addition to those listed for all NSAIDs)
Antacids (concurrent chronic use may significantly decrease the plasma concentration of diflunisal)

For fenoprofen (in addition to those listed for all NSAIDs)
Antacids (concurrent chronic use may significantly decrease the plasma concentration of fenoprofen)

Phenobarbital (phenobarbital may increase metabolism of fenoprofen by inducing hepatic microsomal enzymes, leading to a decrease in the elimination half-life of fenoprofen; fenoprofen dosage adjustment may be required)

For indomethacin (in addition to those listed for all NSAIDs)
Aminoglycosides (administration of indomethacin to neonates being treated for a patent ductus has decreased the renal clearance and increased the plasma concentration of concurrently administered aminoglycoside antibiotics; although not documented, similar effects may occur in other patients, leading to increased risk of toxicity; adjustment of aminoglycoside dosage may be required)

» Zidovudine (indomethacin may competitively inhibit hepatic glucuronidation and decrease the clearance of zidovudine, possibly leading to potentiation of zidovudine toxicity; indomethacin toxicity may also be increased; concurrent use of the two medications should be avoided)

For phenylbutazone (in addition to those listed for all NSAIDs)

Note: Phenylbutazone induces hepatic microsomal enzymes and is itself metabolized by the same enzymes. It has been reported to increase the metabolism of several medications metabolized by hepatic microsomal enzymes and to decrease the metabolism of others. Although not documented, it has been proposed that, in some cases, phenylbutazone may compete with other medications for the enzymes.

Alcohol (concurrent use of alcohol with phenylbutazone may increase the potential for impairment of psychomotor skills)

Anticonvulsants, hydantoin, especially» Phenytoin (phenylbutazone may displace hydantoin anticonvulsants from their protein-binding sites and inhibit their metabolism, possibly leading to increased elimination half-life and toxicity; hydantoin dosage adjustment, based on monitoring of plasma concentrations and/or observed signs of toxicity, may be required)

Barbiturates or
Cortisone (phenylbutazone may decrease the efficacy of these medications by inducing hepatic microsomal enzymes and increasing their metabolism; the possibility should be considered that corticosteroids other than cortisone may be similarly affected)

Cholestyramine (cholestyramine may decrease absorption of phenylbutazone; administration of phenylbutazone 1 hour before or 4 to 6 hours after cholestyramine may decrease the risk of impaired absorption and of toxicity resulting from sudden increases in absorption and serum concentration of phenylbutazone if cholestyramine therapy is discontinued)

Contraceptives, estrogen-containing, oral (concurrent long-term use with phenylbutazone may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding)

» Digitalis glycosides, possibly excepting digoxin (phenylbutazone may increase the hepatic metabolism of digitalis, leading to a decrease in digitalis serum concentration; digitalis glycoside dosage adjustment may be necessary during and following concurrent use)

Sulfonamides (sulfonamides may displace phenylbutazone from its protein binding sites and potentiate its effects; phenylbutazone has also been reported to potentiate the effects of sulfonamides)

Other medications, oral, especially:» Ciprofloxacin {277}» Enoxacin {278}» Itraconazole {279}» Ketoconazole {280}» Lomefloxacin {281}» Norfloxacin {282}» Ofloxacin {283}» Tetracyclines, oral (antacids present in buffered phenylbutazone formulations may decrease absorption of many other orally administered medications by forming nonabsorbable complexes and/or increasing intragastric pH; if used concurrently, buffered phenylbutazone should be taken at least 6 hours before or 2 hours after ciprofloxacin or lomefloxacin, 8 hours before or 2 hours after enoxacin, 2 hours after itraconazole, 3 hours before or after ketoconazole, 2 hours before or after norfloxacin or ofloxacin, 1 to 3 hours before or after tetracycline, and at least 1 to 2 hours before or after other orally administered medications)

For sulindac (in addition to those listed for all NSAIDs)
Antacids (concurrent chronic use may significantly decrease the plasma concentration of sulindac)

Dimethyl sulfoxide (DMSO) (topical application of DMSO to arthritic joints [not recommended because safety and efficacy are unproven] by patients receiving sulindac has been reported to cause peripheral neuropathy and to decrease the plasma concentration of sulindac's active metabolite, thereby decreasing its efficacy)

For tenoxicam (in addition to those listed for all NSAIDs)
Cholestyramine (cholestyramine decreased the average half-life of an intravenous dose of tenoxicam from 67.4 to 31.9 hours and increased the apparent clearance of tenoxicam by 105%)

{180}For tiaprofenic acid (in addition to those listed for all NSAIDs)
Anticonvulsants, hydantoin, especially» Phenytoin (tiaprofenic acid may displace hydantoin anticonvulsants from their protein-binding sites, which may lead to an increase in the concentration of the unbound fraction and to toxicity; hydantoin dosage adjustment, based on monitoring of plasma concentrations and/or observed signs of toxicity, may be required)

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

For fenoprofen:
Triiodothyronine (T 3) determinations (fenoprofen may interfere with total and free T 3 determinations in the Amerlex-M kit assay; thyroid-stimulating hormone, total thyroxine, and thyrotropin-releasing hormone test responses are not affected {26})

For indomethacin:
Dexamethasone suppression test for endogenous depression (indomethacin may produce false-negative test results [i.e., no indication of endogenous depression] because plasma cortisol concentration is reduced to a greater extent than with dexamethasone alone)

For ketoprofen:
Albumin, urine, determinations and
Bile salts, urine, determinations and
17-Ketosteroid (17-KS), urine, determinations and
17-Hydroxycorticosteroid (17-OHCS), urine, determinations (ketoprofen metabolites in urine may interfere with test procedures that rely on acid precipitation as an end point or on color reactions of carbonyl groups; no interference occurs in tests for urinary protein using commercially available dye-impregnated test strips)

For mefenamic acid:
Bile, urinary, determinations (false-positive test results may occur when the diazo tablet test is used; the Harrison test is not affected)

For naproxen:
5-HIAA, urine, determinations (naproxen may interfere with some assays)

Steroid, urine, determinations (17-ketogenic steroid concentrations may be falsely increased by naproxen when m-dinitrobenzene reagent is used; although 17-hydroxycorticosteroid measurements are not significantly altered when the Porter-Silber test is used, naproxen therapy should be discontinued 72 hours before adrenal function tests are performed)

For tolmetin:
Protein, urine, determinations (the metabolites of tolmetin in urine produce false-positive tests for urine protein when the sulfosalicylic acid method is used; no interference occurs in tests for urine protein when commercially available dye-impregnated reagent strips are used)

With physiology/laboratory test values
Bleeding time (may be prolonged by most NSAIDs [with ketoprofen, by 3 to 4 minutes above baseline values] because of suppressed platelet aggregation; effects may persist for less than 1 day [flurbiprofen, ibuprofen, indomethacin, sulindac], 2 days [tolmetin], 4 days [naproxen], or 2 weeks [oxaprozin and piroxicam] following discontinuation of therapy)

(effects on platelet aggregation and bleeding time appear minimal with usual doses of diclofenac, {158}{218} meclofenamate, {37} or mefenamic acid, {38} up to 1000 mg twice a day of diflunisal, or up to 1000 mg per day of nabumetone {210}{250}{251}{252})

Glucose concentrations (decrease in blood glucose concentration has been reported with ibuprofen, indomethacin, and piroxicam)

(increase in blood glucose concentration has been reported with indomethacin, phenylbutazone, piroxicam, and sulindac)

(increase in urine glucose concentration has also been reported with indomethacin )

Hematocrit or
Hemoglobin (values may be decreased, possibly because of gastrointestinal bleeding or microbleeding and/or hemodilution caused by fluid retention {177})

(the incidence of significantly increased transaminase values is higher with diclofenac than with other NSAIDs; in clinical trials with diclofenac, elevations to more than 3 times the upper limit of normal occurred with overall rates of 2% in patients treated for 2 months and 4% in patients treated for 2 to 6 months; values in excess of 8 times the upper limit of normal occurred in approximately 1% of the patients {158})

Plasma renin activity (PRA) (indomethacin has been reported to decrease PRA and to block the increase in PRA usually produced by bumetanide, furosemide, or indapamide)

Uric acid concentrations (serum concentrations may be decreased and urine concentrations increased by diclofenac, {51} diflunisal, {24} etodolac, {177} oxaprozin, {253}{254} and phenylbutazone {224}; in clinical trials with etodolac, the serum concentration was usually decreased by 1 to 2 mg per 100 mL [59 to 118 micromoles/L] after 4 weeks of therapy with 600 to 1000 mg per day and the reduction was maintained during the study period {177})

For mefenamic acid only
Prothrombin time (may be prolonged)

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:

For all NSAIDs:» Allergic reaction, severe, such as anaphylaxis or angioedema, induced by aspirin or other NSAIDs, history of or» Nasal polyps associated with bronchospasm, aspirin-induced (high risk of severe allergic reactions because of cross-sensitivity)

For diclofenac (in addition to those listed for all NSAIDs):» Blood dyscrasias, active or history of or» Bone marrow depression (diclofenac may induce or exacerbate these conditions)

For phenylbutazone (in addition to those listed for all NSAIDs):» Blood dyscrasias, active or history of or» Bone marrow depression (phenylbutazone may induce or exacerbate these conditions)

Conditions predisposing to gastrointestinal toxicity, such as: {01}
Alcoholism, active {295}» Inflammatory or ulcerative disease of the upper or lower gastrointestinal tract, including Crohn's disease, diverticulitis, peptic ulcer disease, or ulcerative colitis, active or history of {160}{168}{169}{174}{175}{182}{187}{189}{211}{213}{216}{218}
Tobacco use, or recent history of {295} (NSAIDs should preferably not be given to patients with active peptic ulcer disease or gastrointestinal bleeding; if NSAID administration is considered essential, an antiulcer regimen should be administered concurrently {303})

(caution and close supervision are also recommended for other patients in whom there is a significant risk of gastrointestinal toxicity; misoprostol or sucralfate should be considered as prophylaxis for those at high risk {303})

» Hemophilia or other bleeding problems including coagulation or platelet function disorders (increased risk of bleeding because most NSAIDs inhibit platelet aggregation and may cause gastrointestinal ulceration or hemorrhage; although the risk of these problems is lower with nabumetone than with most other NSAIDs, caution is recommended {284})

(most NSAIDs are metabolized hepatically; impairment of metabolism may be particularly problematic for nabumetone, since metabolism to the active metabolite 6-MNA may be decreased {210}{211}{285} sufficiently to reduce efficacy {285})

(although stable hepatic cirrhosis does not alter the clearance of etodolac, the possibility should be considered that unstable hepatic disease or severe hepatic function impairment may do so {177})

(hepatic function impairment, especially if associated with chronic alcoholic cirrhosis, produces variability in ketoprofen pharmacokinetics and reduces ketoprofen protein binding; the concentration of unbound ketoprofen may be doubled; caution and careful monitoring are recommended; also, only immediate-release ketoprofen dosage forms should be used if the patient's serum albumin is lower than 3.5 grams per deciliter {205})

(hepatic cirrhosis, especially if associated with chronic alcoholism, increases the concentration of unbound naproxen, even though the total plasma concentration may be decreased; the lowest effective dose should be administered and the patient carefully monitored {188})

(although the clearance of oxaprozin is not altered by well-compensated hepatic cirrhosis, caution is recommended in patients with severe hepatic function impairment {163})

(biotransformation of sulindac to the active sulfide metabolite is slowed; however, biliary elimination of the metabolite is greatly decreased, leading to increased and prolonged plasma concentrations and increased risk of toxicity; the patient should be carefully monitored and dosage adjusted as necessary )

(NSAIDs and/or their metabolites are excreted primarily via the kidneys; a reduction in dosage may be required to prevent accumulation)

(etodolac has not been shown to increase the risk of renal toxicity, and the pharmacokinetic profile of etodolac is not altered, when up to 500 mg of etodolac is administered every 12 hours to patients with mild to moderate renal function impairment; however, the possibility of renal toxicity associated with a reduction of renal prostaglandin synthesis leading to a decrease in renal blood flow cannot be discounted; caution and monitoring of patients considered to be at risk are recommended {177}{232}{262}{263})

(although less than 1% of the active 6-MNA metabolite of nabumetone is eliminated in the urine unchanged, {250} and increased concentrations of 6-MNA were not measured after administration of a single dose, {286} caution is recommended in patients with renal function impairment because the extent to which metabolites may accumulate and cause adverse effects has not been determined {210})

(in end-stage renal disease, conversion of sulindac to its active metabolite is decreased)

» Renal function impairment (the risk of toxicity associated with accumulation of the NSAID and/or the risk of adverse renal effects may be higher with diflunisal, fenoprofen, indomethacin, and piroxicam than with other NSAIDs; individualization of dosage and especially careful monitoring of the patient are recommended)

» Stomatitis (may be induced by NSAIDs; this symptom of possible NSAID-induced blood dyscrasias may be masked by pre-existing stomatitis)

» Caution is also recommended in geriatric patients, who may be more likely to develop adverse hepatic or renal effects with these medications and in whom gastrointestinal ulceration or bleeding is more likely to cause serious consequences, including fatalities.
Caution is also recommended when an NSAID, especially fenoprofen, is used in patients who developed genitourinary tract problems such as dysuria, cystitis, hematuria, nephritis, or nephrotic syndrome during treatment with another NSAID.
The sodium content of diclofenac sodium, meclofenamate sodium, naproxen sodium, naproxen oral suspension, and tolmetin sodium should be considered when selecting an NSAID for patients who must restrict their sodium intake.For diclofenac (in addition to those listed for all NSAIDs):
Porphyria, hepatic (diclofenac may precipitate an acute attack {158}{218})

For indomethacin (in addition to those listed for all NSAIDs):
Epilepsy or» Mental depression or other psychiatric disturbances or
Parkinsonism (indomethacin may aggravate these conditions)

For mefenamic acid (in addition to those listed for all NSAIDs):» Hypoprothrombinemia, when prothrombin activity is 10 to 20% of normal (increased risk of bleeding, since mefenamic acid may further increase the prothrombin time {209})

For phenylbutazone (in addition to those listed for all NSAIDs):» Polymyalgia rheumatica or» Temporal arteritis (phenylbutazone may aggravate these conditions)

For sulindac (in addition to those listed for all NSAIDs):» Renal calculus or history of (renal calculi containing sulindac metabolites have occurred, rarely, in patients receiving sulindac; it is recommended that the medication be used with caution, and in conjunction with adequate fluid intake, in patients who may be predisposed to calculus formation {223}{306})

For rectal administration (in addition to those listed as applying to oral use of the NSAIDs with rectal dosage forms):» Bleeding, rectal or anal, active or recent history of or» Hemorrhoids or» Lesions, inflammatory, of anus or rectum or» Proctitis or recent history of (may be exacerbated or reactivated)

Patient monitoringThe following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood urea nitrogen (BUN) determinations or
Creatinine concentrations, serum and/or
Potassium concentrations, serum (monitoring may be required at periodic intervals during therapy, especially in patients with documented hepatic or renal function impairment, other patients known or suspected to be at risk for renal function impairment, and/or those taking diuretics concurrently; also, may be required if signs of possible renal toxicity, such as substantial increases in blood pressure, fluid retention, or rapid weight gain occur)

Complete physical examinations, including urinalyses (recommended prior to and at regular frequent intervals during phenylbutazone therapy)

Hematocrit determinations and/or
Hemoglobin determinations and/or
Stool tests for occult blood loss (may be performed at one- to six-month intervals to detect blood loss during prolonged therapy, depending on the individual patient's risk of developing gastrointestinal toxicity; however, these tests [unlike endoscopy, which is not recommended on a routine basis] are not capable of detecting ulcerations that are developing asymptomatically or of predicting whether severe gastrointestinal bleeding is likely to occur {304})

» Hematologic determinations (recommended prior to initiation of phenylbutazone therapy and at regular intervals of 3 to 4 weeks during therapy for patients receiving the medication for periods longer than 1 week)

(although routine monitoring is not necessary during therapy with other NSAIDs, appropriate testing should be performed if symptoms of blood dyscrasias occur)

Liver function tests, especially determination of transaminase (AST [SGOT]; ALT [SGPT]) values (may be required at periodic intervals during indomethacin therapy; also, it is recommended that hepatic function tests be performed within eight weeks following initiation of diclofenac therapy and periodically thereafter {119})

(may also be required at periodic intervals during therapy with other NSAIDs if the patient is known or suspected to be at increased risk of developing hepatic adverse effects)

(although routine monitoring is not necessary for most patients during therapy with NSAIDs other than diclofenac or indomethacin, appropriate tests should be performed if signs and/or symptoms of hepatotoxicity occur)

Ophthalmologic examinations (may be required if vision problems such as blurred vision occur during therapy)

Upper gastrointestinal diagnostic tests (recommended for patients with persistent or severe dyspepsia or other signs of possible gastrointestinal toxicity)

Crystalluria, renal calculi, or ureteral obstruction (blood in urine; difficult, burning, or painful urination; severe pain in lower back, side, or abdomen)—with phenylbutazone, may be composed of uric acid crystals and with sulindac, may be composed of sulindac metabolites

* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents (although their pharmacologic similarity suggests that side effects occurring with one may occur with the others). M=more frequent (3–9%); L=less frequent (1–3%); R=rare(<1%); U=unknown; unless otherwise specified.† Has been reported, but a causal relationship has not been established.‡ Has been reported, but actual frequency of occurrence unknown.§ Frequency of occurrence 10% or higher.# Serious gastrointestinal effects, including ulceration, perforation, and/or bleeding, may occur at any time, with or without warning signs and/or symptoms, during chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). The risk of NSAID-induced gastrointestinal toxicity may increase with the duration of therapy as well as with dosage. In clinical trials with nabumetone, peptic ulceration occurred in approximately 0.3%, 0.5%, and 0.8% of patients treated for 6 months, 1 year, and 2 years, respectively. In clinical trials with other NSAIDs, upper gastrointestinal tract ulceration, bleeding, or perforation occurred in approximately 1% of patients treated for 3 to 6 months and in approximately 2 to 4% of patients treated for 1 year. Risk factors that may increase the risk of NSAID-induced gastrointestinal toxicity, other than those associated with an increased risk of peptic ulcer disease in any patient, have not been identified.** See also Dermatologic effects, Hematologic effects, Hepatic effects, and Renal effects for signs and symptoms of many of the reported components of this syndrome.†† Diarrhea occurring during mefenamic acid therapy requires medical attention.

Note:Hypersensitivity reactions with these medications may be similar to those reported for aspirin, i.e., rhinosinusitis/asthma or angioedema/urticaria. Anaphylaxis has also been reported, both in aspirin-sensitive patients and in those without known hypersensitivity to any of these agents. The risk of anaphylaxis, characterized by respiratory distress, circulatory collapse, and angioedema and/or urticaria with or without pruritus, may be increased when previously discontinued therapy with one of these medications is reinstituted. Although anaphylaxis occurs rarely with these agents, several reports have indicated a higher incidence of anaphylactic reactions with tolmetin than with the others.

Other hypersensitivity reactions affecting multiple body systems have also been reported with several of the NSAIDs. A hypersensitivity syndrome consisting of fever and chills, skin rashes or other cutaneous manifestations, hepatotoxicity, renal toxicity (including renal failure), leukopenia, thrombocytopenia, eosinophilia, inflamed glands or lymph nodes, and arthralgias has been reported rarely with diflunisal and with sulindac. Fever, skin rashes, and arthralgias have also preceded fenoprofen-induced renal toxicity. {03} In addition, a syndrome of fever and chills, nausea, vomiting, and abdominal pain has been reported with ibuprofen, {31} and a serum sickness– or influenza-like syndrome that may consist of troubled breathing, arthralgias, fever and chills, fatigue, pruritus, and/or skin rash or other cutaneous manifestations, has been reported with ibuprofen (although a positive causal relationship has not been established), meclofenamate, phenylbutazone, piroxicam, and tolmetin. {44}{45}

The antipyretic, analgesic, and anti-inflammatory actions of NSAIDs may mask symptoms of the occurrence or worsening of infections. Reactivation of latent pulmonary tuberculosis has been reported in a few patients receiving indomethacin. {32}{131}

Two cases of biliary obstruction associated with sulindac therapy have been reported. The obstruction was caused in each case by the presence in the common bile duct of a “sludge” of crystals containing a sulindac metabolite. {305}{308}

Metabolic acidosis and respiratory alkalosis have also been reported rarely (incidences < 1%) with phenylbutazone.

Patients 40 years of age and older may be more susceptible to the toxic effects of phenylbutazone. In patients 60 years of age and older, there is an increased risk of severe, possibly fatal, toxic reactions.

Phenylbutazone-induced agranulocytosis may occur with a rapid onset, especially in relatively young patients. Aplastic anemia may occur more frequently in patients receiving prolonged therapy, especially older female patients. Both agranulocytosis and aplastic anemia are more likely to occur in geriatric patients.

Because diflunisal is a salicylic acid derivative, the possibility that it may be associated with the development of Reye's syndrome in children, teenagers, or young adults with acute febrile illnesses, especially influenza or varicella, should be kept in mind. {24}

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Acute and chronicFor phenylbutazoneBluish color of fingernails, lips, or skinconvulsions, especially in childrendifficulty in hearing or ringing or buzzing in the earsdizziness or lightheadednesshallucinationsheadache, severe and continuingincrease or decrease in blood pressuremood or mental changesnausea, vomiting, or stomach pain, severeperiorbital edema (swelling around the eyes)shortness of breath, troubled breathing, or unusually slow, fast, or irregular breathingswelling of face, hands, feet, or lower legsNote: The lowest fatal doses reported for phenylbutazone are 14 grams (in an adult) and 2 grams (in a 3-year-old child). The highest doses reported to have been survived are 40 grams (in a young adult) and 5 grams (in a 3-year-old child).
Laboratory findings in overdose may reveal respiratory or metabolic acidosis or alkalosis, other electrolyte disturbances, impaired hepatic or renal function, and abnormalities of formed blood elements.
Late manifestations of massive overdosage may occur 2 to 7 days following ingestion and may include hepatomegaly, jaundice, electrocardiographic abnormalities, blood dyscrasias, and ulceration of the buccal or gastrointestinal mucosa.

For other NSAIDs

Note: The symptoms of overdose of most of the other NSAIDs have not been described as completely as for phenylbutazone. Reported symptoms have generally reflected the gastrointestinal, renal, and CNS toxicities of these medications. Following overdosage with a propionic acid derivative or indomethacin, patients may remain asymptomatic or experience only relatively mild CNS effects (e.g., lethargy, drowsiness) or gastrointestinal symptoms (e.g., abdominal pain, nausea, vomiting). However, more serious effects, such as gastrointestinal hemorrhage, acute renal failure, convulsions, and coma have been reported with these, as well as other, NSAIDs. Convulsions may be especially likely to occur following mefenamic acid overdose. Also, hypoprothrombinemia has been reported following overdose of several NSAIDs. {95}

Treatment of overdose
To decrease absorption—Emptying the stomach via induction of emesis (in alert patients only) or gastric lavage. However, syrup of ipecac may induce symptoms similar to those of NSAID toxicity, which may complicate diagnosis, and is therefore not recommended for induction of emesis. {95}

Administering activated charcoal. The efficacy of activated charcoal in decreasing absorption of these medications when given more than 2 hours (6 hours for piroxicam) following ingestion of the overdose has not been determined. However, there is some evidence that repeated administration of activated charcoal may interrupt enterohepatic circulation and/or bind any of the medication that has diffused from the circulation into the intestine, thereby increasing nonrenal excretion. {95}

To enhance elimination—Administering antacids or other urinary alkalizers may increase diflunisal or sulindac excretion. Antacids may also relieve adverse gastrointestinal effects.

Inducing diuresis may be helpful in overdosage with fenoprofen, ibuprofen, or tolmetin; however, furosemide does not lower fenoprofen blood concentration.

Hemodialysis may be necessary to treat renal failure, but cannot be relied upon to decrease plasma concentrations of most NSAIDs because of their high degree of protein binding. Studies have shown that diclofenac and ketoprofen are dialyzable, but that diflunisal, etodolac, ibuprofen, indomethacin, and oxaprozin are not.

Specific treatment—

For severe hypotension plasma:

Use of volume expanders

For convulsions:

Diazepam or other appropriate benzodiazepine anticonvulsants. See the package insert or Diazepam in Benzodiazepines (Systemic) for specific dosing guidelines for use of this product.

For hypoprothrombinemia:

Use of Vitamin K 1. See the package insert or Vitamin K 1—Phytonadione in Vitamin K (Systemic) monograph for specific dosing guidelines for use of this product.

Instituting symptomatic and other supportive treatment as necessary. Certain adverse effects of NSAIDs, including nephritis or nephrotic syndrome, thrombocytopenia, hemolytic anemia, and severe cutaneous or other hypersensitivity reactions, may respond to glucocorticoid administration. {96}{97}

Monitoring—The possibility must be considered that gastrointestinal ulceration or hemorrhage, and phenylbutazone-induced blood dyscrasias, may occur several days after ingestion of an overdose. Patients being discharged after initial treatment should be informed of possible presenting symptoms and advised to seek immediate treatment if they occur.

Supportive care—Monitoring and supporting vital functions. If respiratory support is required following phenylbutazone overdose, respiratory stimulants should not be used. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anti-inflammatory Drugs, Nonsteroidal (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):Before using this medication» Conditions affecting use, especially:Allergies to aspirin or any of the nonsteroidal anti-inflammatory drugs (NSAIDs)

Pregnancy—Use of an NSAID during second half of pregnancy not recommended because of potential adverse effect on fetal blood flow and possible prolongation of pregnancy, dystocia, and difficult and/or delayed delivery

Breast-feeding—For indomethacin: Has caused convulsions in a nursing infant

For meclofenamate and piroxicam: These NSAIDs have caused adverse effects in animal studies

For phenylbutazone: May cause blood dyscrasias or other adverse effects in the infant

Use in children—For indomethacin: Because of toxicity, should be used with caution and only in patients unresponsive to less toxic NSAIDs

For naproxen: Skin rash more common in pediatric patients

For phenylbutazone: Because of toxicity, not recommended in children < 15 years of age

• For indomethacin (in addition to those applying to all NSAIDs): Epilepsy, mental illness, and parkinsonism

• For phenylbutazone (in addition to those applying to all NSAIDs): Polymyalgia rheumatica and temporal arteritis

• For sulindac (in addition to those applying to all NSAIDs): Renal calculus or history of

• For rectal dosage forms (in addition to those applying to oral use of the NSAIDs with rectal dosage forms): Anal or rectal bleeding, hemorrhoids, inflammatory lesions of anus or rectum, and proctitis or recent history of

Proper use of this medication

For all NSAIDs» Not taking more medication than prescribed or recommended on OTC package label

» For use in arthritis—Compliance with therapy; noticeable improvement in condition usually requires a few days to a week of treatment (but up to 2 weeks, and sometimes even longer, in severe cases) and maximum effectiveness may require several weeks of treatment

For flurbiprofen extended-release tablets, nabumetone, and naproxen extended-release tablets
Taking with food or antacids (a magnesium- and aluminum-containing antacid may be preferred) to reduce gastrointestinal irritation; taking with food also increases absorption

For immediate-release and extended-release oral dosage forms of NSAIDs not listed above
Taking with food or antacids (a magnesium- and aluminum-containing antacid may be preferred) to reduce gastrointestinal irritation, although when used for acute conditions (e.g., pain, gout, fever, or dysmenorrhea) the first 1 or 2 doses may be taken on an empty stomach to speed the onset of action

For oral suspensions
Not mixing suspension with an antacid or other liquid prior to use

For delayed-release (enteric-coated) or extended-release dosage forms, diflunisal tablets, and all phenylbutazone tablet formulations
Swallowing whole; not breaking, chewing or crushing before swallowing

For all suppository dosage forms
Proper administration technique

For indomethacin suppositories
Retaining in rectum for 1 full hour to ensure maximum absorption

For nonprescription use of ibuprofen or naproxen» Reading patient information sheet provided in package

For phenylbutazone» Taking for prescribed indications only; not taking to relieve other aches and pains

For mefenamic acid» Not taking longer than 7 days at a time unless otherwise directed by physicianPrecautions while using this medication» Regular visits to physician during prolonged therapy

» Possibility that use of alcohol may increase the risk of ulceration and, with phenylbutazone, depressant effects

» Checking with physician if you consume 3 or more alcohol-containing beverages per day; alcohol consumption may increase the risk of NSAID-induced gastrointestinal toxicity

Not taking 2 or more NSAIDs, including ketorolac, concurrently, and not taking acetaminophen or aspirin or other salicylates for more than a few days while receiving NSAID therapy, unless concurrent use is prescribed by, and patient remains under the care of, a physician or dentist

Caution if any surgery is required because of possible enhanced bleeding (although may be less of a problem with diclofenac, diflunisal, meclofenamate, mefenamic acid, and nabumetone)

» Notifying physician immediately if influenza-like symptoms (chills, fever, or muscle aches and pains) occur shortly prior to or together with a skin rash; rarely, these symptoms may indicate a serious reaction to the medication

Possibility of anaphylaxis

For buffered phenylbutazone» Not taking within: —6 hours before or 2 hours after ciprofloxacin or lomefloxacin
—8 hours before or 2 hours after enoxacin
—2 hours after itraconazole
—3 hours before or after ketoconazole
—2 hours before or after norfloxacin or ofloxacin
—1 to 3 hours before or after an oral tetracycline

For mefenamic acid
Discontinuing use and checking with physician if severe diarrhea occurs

For nonprescription use of ibuprofen or naproxen
Checking with health care professional if symptoms do not improve or if they worsen, if using for fever and fever lasts more than 3 days or returns, or if painful area is red or swollen

Side/adverse effects»Stopping medication and obtaining emergency treatment if symptoms of any of the following occur

For all NSAIDs
Anaphylaxis, angioedema, or bronchospasm»Stopping medication and checking with physician immediately if symptoms of the following occur

For indomethacin (in addition to those applying to all NSAIDs) Headache (severe), especially in the morning

Possibility that the following may occur many days or weeks after medication is discontinued

For phenylbutazone
Blood dyscrasias

General Dosing Information
The sodium content of diclofenac sodium, meclofenamate sodium, naproxen sodium, naproxen oral suspension, and tolmetin sodium should be considered when selecting a nonsteroidal anti-inflammatory drug (NSAID) for patients who must restrict their sodium intake. Also, the sucrose content of ibuprofen and naproxen suspensions must be considered when selecting an NSAID for patients who must restrict their sucrose intake.

Patients who do not respond to one NSAID may respond to another. In responsive patients, partial symptomatic relief of arthritic symptoms usually occurs within 1 or 2 weeks, although maximum effectiveness may occur only after several weeks of therapy.

A reduction of initial dosage, possibly to as low as one-half the usual adult dose, is recommended for geriatric patients, especially those 70 years of age or older. However, if the reduced dose fails to produce an adequate clinical response and the medication is well tolerated, dosage may be increased as required and tolerated.

A reduction of dosage may also be required to prevent accumulation of NSAIDs and/or their metabolites (some of which may be unstable and may be hydrolyzed to the parent compound when their excretion is delayed) in patients with renal function impairment.

Long-term use of NSAIDs in doses that approach or exceed maximum dosage recommendations should be considered only if the clinical benefit is increased sufficiently to offset the higher risk of gastrointestinal toxicity or other adverse effects. {123}

Indomethacin, mefenamic acid, phenylbutazone, and piroxicam should be administered immediately after meals or with food or antacids to reduce gastrointestinal irritation. Flurbiprofen extended-release capsules, nabumetone, or naproxen extended-release tablets should also be taken with food to increase absorption as well as reduce gastrointestinal irritation. The other NSAIDs (except for delayed-release [enteric-coated] and rectal dosage forms) are also preferably taken after meals or with food or antacids to reduce gastrointestinal irritation, especially during chronic use; however, for faster absorption when a rapid initial effect is required (as for analgesic or antipyretic use), the first 1 or 2 doses may be taken 30 minutes before meals or at least 2 hours after meals. If an antacid is taken concurrently, an aluminum- and magnesium–containing formulation may be preferred, since studies have shown that this formulation does not adversely affect absorption of most NSAIDs (See Table 1.

It is recommended that solid oral dosage forms of NSAIDs be taken with a full glass (240 mL) of water and that the patient remain in an upright position for 15 to 30 minutes after administration. These measures may reduce the risk of tablets or capsules becoming lodged in the esophagus, which has been reported to cause prolonged esophageal irritation and difficulty in swallowing in some patients receiving these medications.

In the treatment of primary dysmenorrhea, maximum benefit is achieved by initiating NSAID therapy as rapidly as possible after the onset of menses. {07}{31}{38} Prophylactic therapy (i.e., starting NSAID administration a few days prior to the expected onset of the menstrual period) has not been found to provide additional therapeutic benefit. {07}

Concurrent use of an NSAID with an opioid analgesic provides additive analgesia and may permit lower doses of the opioid analgesic to be utilized.

The analgesic activity of non-opioid analgesics is subject to a ceiling effect. Therefore, administration of an NSAID in higher-than-recommended analgesic doses may not provide additional therapeutic benefit in the treatment of pain not associated with inflammation.

In the treatment of arthritis, most of these agents have been shown to provide additional symptomatic relief when administered concurrently with gold compounds or glucocorticoids. NSAIDs may permit reduction of glucocorticoid dosage; however, reductions of glucocorticoid dosage, especially following long-term use, should be gradual to avoid symptoms associated with adrenal insufficiency or other manifestations of too-sudden withdrawal.

DICLOFENAC

Summary of Differences

Indications:
Indicated for rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Immediate-release tablets only indicated for pain and primary dysmenorrhea, and may also be used to relieve acute attacks of gout or calcium pyrophosphate deposition disease (pseudogout) and pain associated with nonrheumatic inflammatory conditions or vascular headaches.

Diclofenac therapy should be discontinued if gastrointestinal bleeding or ulceration occurs.For oral dosage forms only
The delayed-release tablets and the extended-release tablets are to be swallowed whole, not crushed or chewed.

Oral Dosage FormsDICLOFENAC POTASSIUM TABLETSUsual adult dose
Analgesic and
Antidysmenorrheal
Oral, 50 mg three times a day as needed. If necessary, 100 mg may be administered for the first dose only. {158}{215}

Rheumatoid arthritis
Oral, 150 to 200 mg per day in three or four divided doses, initially. {158} After a satisfactory response has been obtained, dosage should be reduced to the minimum dose that provides continuing control of symptoms, {23}{119}{158}{217} usually 75 to 100 mg a day in three divided doses. {23}{217}

Osteoarthritis
Oral, 100 to 150 mg per day in two or three divided doses, initially. {119}{158}{217} After a satisfactory response has been obtained, dosage should be reduced to the minimum dose that provides continuing control of symptoms. {23}{119}{158}{217}

Ankylosing spondylitis 1
Oral, 100 to 125 mg a day in four or five divided doses, initially. After a satisfactory response has been obtained, dosage should be reduced to the minimum dose that provides continuing control of symptoms. {119}{158}

Usual adult prescribing limits
Analgesic and
Antidysmenorrheal
Up to 200 mg on the first day, then 150 mg per day thereafter. {158}{218}

DICLOFENAC SODIUM DELAYED-RELEASE TABLETSUsual adult dose
Analgesic
and Antidysmenorrheal
The delayed-release formulation is not recommended. See Diclofenac Potassium Tablets , which should be used for these indications.

DICLOFENAC SODIUM EXTENDED-RELEASE TABLETSUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 75 or 100 mg once a day, in the morning or evening, or 75 mg two times a day, in the morning and evening. {217}

Note: The extended-release dosage form is not intended as initial therapy; the daily maintenance dose should be determined using an immediate- or delayed-release formulation. {217} The extended-release dosage form may then be used, if desired, provided that the required dose can be achieved with the available strengths.

Usual pediatric dose
Safety and efficacy have not been established.Strength(s) usually available
U.S.—
Not commercially available.

Usual adult prescribing limits
Total daily dosage (oral and rectal) should not exceed 150 mg. {23}{217}Usual pediatric dose
Safety and efficacy have not been established.Strength(s) usually available
U.S.—
Not commercially available.

Indications:
Indicated for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and psoriatic arthritis, and pain. May also be used to relieve acute attacks of gout or calcium pyrophosphate deposition disease (pseudogout), dysmenorrhea, and pain associated with nonrheumatic inflammatory conditions or vascular headaches.

Pharmacology/pharmacokinetics:
Physicochemical characteristics—Chemical group: A salicylate derivative, although not metabolized to salicylate in vivo .

Diflunisal also increases plasma concentration of hydrochlorothiazide and decreases hyperuricemic effect of hydrochlorothiazide or furosemide, but has not been shown to decrease furosemide-induced diuresis.

Administration of a 1-gram initial loading dose is recommended to provide faster onset of analgesic action, shorter time to peak analgesic effect, and greater peak analgesic action. For long-term use, the initial loading dose decreases the time needed to reach steady-state plasma concentrations; if a loading dose is not administered, 2 to 3 days may be required to evaluate changes in treatment regimens.

In patients with impaired renal function, especially if renal function is decreased to 1/2 the normal value or below, a reduction in dosage and/or an increase in the dosing interval may be necessary to prevent diflunisal accumulation.

Tablets are to be swallowed whole, not crushed or chewed.

Because diflunisal is not hydrolyzed to salicylic acid in vivo , serum salicylate concentration cannot be used as a guide to dosage or potential toxicity during therapy.

Oral Dosage FormsDIFLUNISAL TABLETS USPUsual adult dose {24}{164}{165}{219}{267}
Rheumatoid arthritis or
Osteoarthritis
Oral, 250 to 500 mg two times a day; dosage may be increased or decreased according to patient response.

Analgesic
Oral, 1 gram initially, followed by 500 mg every eight to twelve hours as needed.

Note: For some patients, 500 mg initially followed by 250 mg every eight to twelve hours may be appropriate, depending on the severity of pain or the age, weight, or response of the patient.

Usual adult prescribing limits
Up to 1.5 grams daily. {24}{164}{219}Usual pediatric dose
Dosage has not been established.Strength(s) usually available
U.S.—

Indications:
Indicated for treatment of osteoarthritis and for pain. May also be used to relieve acute attacks of gout or calcium pyrophosphate deposition disease (pseudogout), dysmenorrhea, and pain associated with nonrheumatic inflammatory conditions or vascular headaches.

Oral Dosage FormsETODOLAC CAPSULESUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 400 mg two or three times a day or 300 mg three or four times a day, initially. After a satisfactory response has been obtained, dosage should be individualized according to patient tolerance and response. Most patients are maintained on 600 to 1200 mg per day. However, as little as 200 mg two times a day has been effective in some patients. {177}

Note: Although doses of up to 1 gram per day have been effective when administered in two divided doses (500 mg every twelve hours), administration on a three-dose-a-day schedule may provide greater benefit. {177}

Analgesic
Oral, 400 mg initially, then 200 to 400 mg every six to eight hours as needed. If a 400-mg dose fails to provide eight hours of analgesia, a regimen of 300 mg every six hours may be effective. {177}

Usual adult prescribing limits
1000 mg a day {316}.Usual pediatric dose
Safety and efficacy have not been established {316}.Usual geriatric dose
See Usual adult dose{316}.Strength(s) usually available
U.S.—

Indications:
Indicated for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and psoriatic arthritis; pain; and acute attacks of gout or calcium pyrophosphate deposition disease (pseudogout). May also be used to relieve dysmenorrhea and pain associated with nonrheumatic inflammatory conditions or vascular headaches. Also used for vascular headache prophylaxis.

In the treatment of arthritis, improvement in condition may occur within a few days, but 2 to 3 weeks of continuous use on a regular basis may be required for maximum effectiveness.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling. The dosing and strengths of the available dosage forms are expressed in terms of the free acid (not the calcium salt).FENOPROFEN CALCIUM CAPSULES USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 300 to 600 mg (free acid), depending on the severity of the symptoms, three or four times a day, then adjusted as needed. {186}

Note: Higher doses generally are required in rheumatoid arthritis than in osteoarthritis.

600 mg (free acid) (Rx) [Nalfon{187}]Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a well-closed container.Auxiliary labeling:
• Take with food.
• Take with a full glass of water.
• May cause drowsiness.
• Avoid alcoholic beverages.1 Not included in Canadian product labeling.

FLOCTAFENINE

Summary of Differences

Indications:
Indicated for relief of pain. May also be used to relieve acute attacks of gout or calcium pyrophosphate deposition disease (pseudogout), dysmenorrhea, and pain associated with nonrheumatic inflammatory conditions or vascular headaches.

Precautions:
Pregnancy/reproduction—Embryotoxicity but not teratogenicity demonstrated in animal studies.

Drug interactions and/or related problems—Floctafenine-induced increase in effect of coumarin- or indanedione-derivative anticoagulants may not become apparent until after 2 weeks of concurrent use.

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.FLURBIPROFEN EXTENDED-RELEASE CAPSULESUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 200 mg once a day in the evening. {169}

Note: The extended-release dosage form is not intended as initial therapy; the daily maintenance dose should be determined using the immediate-release formulation. {169} The extended-release dosage form may then be used, if desired, provided that the required dose can be achieved with the available strength.

Usual pediatric dose
Safety and efficacy have not been established.Strength(s) usually available
U.S.—
Not commercially available.

FLURBIPROFEN TABLETS USPUsual adult dose
Rheumatoid arthritis or
Osteoarthritis
Oral, 200 to 300 mg a day in two to four divided doses, initially. Dosage may then be individualized according to the severity of the disease and patient response. {126}{144}
[Ankylosing spondylitis ]
Oral, 200 mg a day in four divided doses, initially, although some patients may require 250 to 300 mg a day. {169}

Note: After a satisfactory response has been obtained, dosage should be decreased to the lowest dose that provides continuing control of symptoms. {169}

[Anti-inflammatory (nonsteroidal) ]
Oral, 50 mg every four to six hours as needed. {145}{220}

Usual adult prescribing limits
The maximum recommended single dose is 100 mg. {126}{144} Total daily dosage should not exceed 300 mg. {144}{169} This maximum dose is recommended for short-term use only, i.e., for initiation of therapy or for treating acute exacerbations of symptoms; it should not be used as a maintenance dose. {29}{145}{169}Usual pediatric dose
Safety and efficacy have not been established.Strength(s) usually available
U.S.—

Indications:
Indicated for rheumatoid arthritis, osteoarthritis, juvenile arthritis, and psoriatic arthritis; pain; gouty arthritis or calcium pyrophosphate deposition disease (pseudogout); fever; and dysmenorrhea. May also be used for prophylaxis and treatment of vascular headaches.

In the treatment of arthritis, improvement in condition may occur within 7 days, but 1 to 2 weeks of continuous use on a regular basis may be required for maximum effectiveness.

Oral Dosage FormsIBUPROFEN ORAL SUSPENSIONUsual adult and adolescent dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 1200 to 3200 mg a day in three or four divided doses. After a satisfactory response has been obtained, dosage should be reduced to the lowest maintenance dose that provides continuing control of symptoms. {129}{130}{183}{222}

Note: Higher doses generally are required in rheumatoid arthritis than in osteoarthritis.

Analgesic (mild to moderate pain)
Antipyretic or
Antidysmenorrheal
Oral, 200 to 400 mg every four to six hours as needed. {31}{128}{129}{137}{138}

Usual adult prescribing limits
Antirheumatic (nonsteroidal anti-inflammatory)
Up to 3600 mg per day. The maximum dosage should be used only if the clinical benefit is increased sufficiently to offset the higher risk of adverse effects. {31}{183}{222}

Usual pediatric dose
Antirheumatic (nonsteroidal anti-inflammatory)
Infants up to 6 months of age: Safety and efficacy have not been established. {128}{139}

Children 6 months to 12 years of age: Oral, initially 30 to 40 mg per kg of body weight a day in three or four divided doses, although 20 mg per kg of body weight per day may be sufficient for patients with mild disease. After a satisfactory response has been achieved, dosage should be reduced to the lowest dose needed to control disease activity. {128}{139}

Antipyretic
Infants up to 6 months of age: Safety and efficacy have not been established. {129}

Children 6 months to 12 years of age: Oral, 5 mg per kg of body weight for fevers less than 39.17 °C (102.5 °F) and 10 mg per kg of body weight for higher fevers. Dosage may be repeated, if necessary, at intervals of 4 to 6 hours or more. {128}{129}{139}{183}

Canada—
Not commercially available.Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a well-closed, light-resistant container, unless otherwise specified by manufacturer.Auxiliary labeling:
• Take with food.
• Take with a full glass of water.
• May cause drowsiness.
• Avoid alcoholic beverages.

Drug of first choice in ankylosing spondylitis; for other indications (except Bartter's syndrome), recommended only for patients unresponsive to less toxic NSAIDs or, in the case of fever, to other antipyretic agents.

Absorption—Oral: Capsules and oral suspension—90% of a dose absorbed within 4 hours.

Extended-release capsules—90% of a dose absorbed within 12 hours.

Rectal: 80 to 90% of a dose absorbed; incomplete absorption may result from failure to retain suppository in rectum for a full hour.

Half-life—Elimination: Average, about 4.5 hours; subject to substantial intersubject variability, possibly because of differences in enterohepatic circulation and subsequent reabsorption.

Onset of action—Gout: 2–4 hours.

Time to peak effect—Gout (capsules or oral suspension): 2–3 days for relief of heat and tenderness; 3–5 days for relief of swelling.

Precautions:
Pregnancy/reproduction—

First trimester: Crosses the placenta; fetotoxic, teratogenic, and other adverse effects demonstrated in animal studies.

Third trimester: Has caused closure of the ductus arteriosus, inhibition of platelet function resulting in bleeding, renal function impairment or failure with oligohydramnios, gastrointestinal bleeding or perforation, and myocardial degenerative changes in fetuses when given to pregnant women during the third trimester.

Breast-feeding—Distributed into breast milk; one report of convulsions in a breast-fed infant exposed to the medication.

Pediatrics—Recommended only for pediatric patients who are unresponsive to or intolerant of less toxic agents. Only immediate-release oral dosage forms should be used. Also, recommended doses should not be exceeded and the patient carefully monitored.

Indomethacin should be administered in the lowest dose that provides symptomatic relief. Doses greater than 150 to 200 mg per day may increase the risk of adverse effects without providing additional clinical benefit. If therapy is to be continued after the acute phase of the disease has been controlled, periodic attempts should be made to reduce the dose to the lowest dose providing continuing control of symptoms.

If minor adverse effects occur, dosage should be reduced and the patient carefully monitored. If severe side effects occur, therapy should be discontinued.

For oral dosage forms only
Oral dosage forms of indomethacin should always be administered after meals or with food or an antacid to reduce gastrointestinal irritation. However, the oral suspension should not be mixed with an antacid or other liquid prior to use.

To facilitate dosage adjustment and assessment of patient tolerance of the medication, it is recommended that an immediate-release, rather than the extended-release, dosage form be used for initiation of therapy or to increase the daily dose. If the extended-release dosage form is used for initial therapy, or to increase the daily dose, careful observation of the patient is recommended.

For rectal dosage form only
To ensure maximum absorption, the suppository should be retained for at least one full hour after insertion.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.INDOMETHACIN CAPSULES USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, initially 25 or 50 mg two to four times a day; if well tolerated, the dosage per day may be increased by 25 or 50 mg at weekly intervals until a satisfactory response is obtained or up to a maximum dose of 200 mg per day. After a satisfactory response has been achieved, dosage should be reduced to the lowest dose that provides continuing control of symptoms. {175}{176}

Note: In acute flare-ups of rheumatoid arthritis, dosage may be increased by 25 or 50 mg daily, as needed and tolerated. {176}
For those arthritic patients who have persistent night pain and/or morning stiffness, up to 100 mg of the total daily dose may be given at bedtime. Lower bedtime doses may not provide adequate symptomatic relief. {176}
A daily dose of less than 75 mg may not be effective in active inflammatory disease.
A daily dose of more than 150 to 200 mg may increase the risk of adverse effects without providing additional clinical benefit. {175}{176}

Antigout agent
Oral, 100 mg initially, then 50 mg three times a day until pain is relieved, with the dosage then being reduced until medication is discontinued.

Anti-inflammatory (nonsteroidal) 1
75 to 150 mg per day in three or four divided doses. {176}

Note: When used to treat conditions not requiring chronic therapy, such as acute bursitis or tendinitis of the shoulder, indomethacin should be discontinued when symptoms of inflammation have been controlled for several days. The usual length of treatment is 7 to 14 days. {176}

Usual adult prescribing limits
Oral, 200 mg a day. {175}{176}Usual pediatric dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 1.5 to 2.5 mg per kg of body weight per day, administered in three or four divided doses, up to a maximum of 4 mg per kg of body weight per day or 150 to 200 mg per day, whichever is less. After a satisfactory response has been obtained, dosage should be reduced to the lowest dose that provides continuing control of symptoms. {176}

INDOMETHACIN EXTENDED-RELEASE CAPSULES USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 75 mg once a day, in the morning or at bedtime; may be increased to 75 mg two times a day if necessary. {175}{176}

Note: It is generally recommended that the daily maintenance dose be determined using the immediate-release formulation. The extended-release dosage form may then be used, if desired, provided that the required dose can be achieved with the available strength.
Careful observation of the patient for signs of intolerance is recommended if the extended-release capsule is used for initiating indomethacin therapy or for increasing the daily dose. Initiation of therapy with one extended-release capsule daily provides the maximum initial dose recommended by the manufacturer. Use of the extended-release capsule to increase the dose provides a greater-than-recommended increase in daily dosage. {32}{176}

Usual pediatric dose
Dosage has not been established.Strength(s) usually available
U.S.—

75 mg (Rx) [Indocid SR{175} (sucrose)]Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.Auxiliary labeling:
• Take with food or antacids.
• Take with a full glass of water.
• Avoid alcoholic beverages.Additional information:
The extended-release capsules are designed to release 25 mg of indomethacin immediately and the remaining 50 mg over a 12-hour period.

Canada—
Not commercially available.Packaging and storage:
Store below 30 °C (86 °F). Store in a tight, light-resistant container. Protect from freezing.Incompatibilities:
Indomethacin is unstable in an alkaline medium and should not be mixed with antacids or other liquids having an alkaline pH.Auxiliary labeling:
• Take with food or antacids.
• Shake well.
• Avoid alcoholic beverages.

Note: A daily dose of less than 75 mg may not be effective in active inflammatory disease.
For those arthritic patients who have persistent night pain and/or morning stiffness, up to 100 mg of the total daily dose may be given at bedtime. Lower bedtime doses may not provide adequate symptomatic relief. {176}
A daily dose of more than 150 to 200 mg may increase the risk of adverse effects without providing additional clinical benefit. {175}{176}

Usual adult prescribing limits
Rectal or combined oral and rectal, 200 mg per day. {175}{176}Usual pediatric dose
Antirheumatic (nonsteroidal anti-inflammatory)
Rectal, 1.5 to 2.5 mg per kg of body weight per day, administered in 3 or 4 divided doses, up to a maximum of 4 mg per kg of body weight or 150 to 200 mg per day, whichever is less. {176}

Precautions:
Pregnancy/reproduction—Fertility: Decreased number of implantation sites in female rats (but no effect on fertility in male rats); high doses caused abnormal spermatogenesis or impaired spermatogenesis in rats and dogs and decreased testicular weight in dogs and baboons.

First trimester: No teratogenicity demonstrated in animal studies; in rabbits, maternally toxic doses shown to be embryotoxic.

Geriatrics—Protein binding and clearance reduced in elderly people, leading to increased plasma concentration and prolonged half-life.

Drug interactions and/or related problems—

Probenecid may greatly increase ketoprofen plasma concentration and the risk of toxicity; concurrent use not recommended.

Studies failed to show that ketoprofen increases digoxin plasma concentration.

Laboratory value alterations—Interference with determinations of urinary albumin, bile salts, 17-ketosteroids, and 17-hydroxycorticosteroids via test procedures that rely on acid precipitation or on color reaction of carbonyl groups as an end point.

Oral Dosage FormsKETOPROFEN CAPSULESUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 150 to 300 mg a day in three or four divided doses, usually 75 mg three times a day or 50 mg four times a day, initially, then adjusted according to patient response. {35}{205}

Analgesic or
Antidysmenorrheal
Oral, 25 {205} to 50 {205}{206} mg every six to eight hours as needed. Dosage may be increased if necessary, but single doses higher than 75 mg have not been shown to provide additional analgesia. {205} In the treatment of dysmenorrhea, 75-mg doses may be more effective than lower doses. {35}{205}

Note: In patients with renal function impairment, a 33 to 50% reduction of dosage is recommended. {35}

Note: The analgesic dosage for self-medication with ketoprofen using the over-the-counter product is 12.5 mg every four to six hours {312}{313}.

Usual adult prescribing limits
Oral, 300 mg a day in three or four divided doses. {205}{206}

Note: Risk/benefit must be considered when the maximum dose is prescribed because the incidence of gastrointestinal effects and headache is increased with administration of 300 mg per day (as compared with 200 mg per day). {35}{205}

Usual pediatric dose
Safety and efficacy have not been established. {205}Strength(s) usually available
U.S.—

Note: The extended-release dosage form is not intended as initial therapy; the daily maintenance dose should be determined using an immediate- or delayed-release formulation. The extended-release dosage form may then be used, if desired, provided that the required dose can be achieved with the available strength(s).

Usual pediatric dose
Safety and efficacy have not been established. {205}Strength(s) usually available
U.S.—

200 mg (Rx) [Oruvail{207}]Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.Auxiliary labeling:
• Swallow capsule whole.
• Take with a full glass of water.
• Avoid alcoholic beverages.Note: The extended-release capsule is formulated with delayed-release as well as extended-release characteristics. Dissolution of the contents of the capsules (coated pellets) does not occur until the medication reaches the alkaline pH of the small intestine.

KETOPROFEN EXTENDED-RELEASE TABLETSUsual adult dose
See Ketoprofen Extended-release Capsules .Usual pediatric dose
Safety and efficacy have not been established.Strength(s) usually available
U.S.—
Not commercially available.

Rectal Dosage FormsKETOPROFEN SUPPOSITORIESUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Rectal, 50 or 100 mg two times a day, in the morning and evening; or 50 or 100 mg in the evening in conjunction with oral administration during the day. {36}{206}

Usual adult prescribing limits
Rectal or combined oral and rectal, 300 mg a day. {206}Usual pediatric dose
Safety and efficacy have not been established. {206}Strength(s) usually available
U.S.—
Not commercially available.

Improvement in condition may occur within a few days, but 2 to 3 weeks of continuous use on a regular basis may be required for maximum effectiveness.

Gastrointestinal side effects may respond to a reduction in dosage; however, if severe adverse reactions occur, therapy should be discontinued.

Oral Dosage Forms

Note: The dosing and strengths of the available dosage form are expressed in terms of meclofenamic acid (not the sodium salt).MECLOFENAMATE SODIUM CAPSULES USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 200 mg (meclofenamic acid) a day, in three or four divided doses, initially. Dosage may be increased to up to 400 mg a day if necessary. After a satisfactory response has been obtained, dosage should be reduced to the lowest maintenance dose that provides continuing control of symptoms. {37}{178}

Analgesic
Oral, 50 mg (meclofenamic acid) every four to six hours. If necessary, dosage may be increased to 100 mg every four to six hours. {127}{178}

Antidysmenorrheal and
Antihypermenorrheal
Oral, 100 mg (meclofenamic acid) three times a day for up to six days. {178}

Canada—
Not commercially available.Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.Auxiliary labeling:
• Take with food.
• Take with a full glass of water.
• Avoid alcoholic beverages.

MEFENAMIC ACID

Summary of Differences

Indications:
Indicated for short-term use (7 days or less) to relieve pain and dysmenorrhea. May also be used for acute attacks of gout or calcium pyrophosphate deposition disease (pseudogout), for pain associated with nonrheumatic inflammatory conditions or vascular headaches, and to prevent migraines associated with menstruation.

Other actions/effects—With usual doses has lesser effect on platelet aggregation than most other NSAIDs.

Half-life—Elimination: 2 hours

Precautions:
Pregnancy/reproduction—

Fertility: Decreased fertility demonstrated in rodents.

Pregnancy: Increased number of resorptions and decreased survival to weaning demonstrated in rodents.

Surgical—With usual doses may be less likely than other NSAIDs to inhibit platelet aggregation significantly, but has been reported to cause hypoprothrombinemia, which may increase the risk of perisurgical bleeding.

It is recommended that mefenamic acid therapy be discontinued promptly if diarrhea or a skin rash develops. Patients who develop diarrhea during mefenamic acid therapy are usually unable to tolerate the drug thereafter.

Oral Dosage FormsNABUMETONE TABLETSUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, initially 1000 mg a day, as a single dose (usually at night) or in two divided doses (in the morning and evening). Dosage may be increased, if necessary, to 1500 mg or 2000 mg a day in two divided doses. After a satisfactory response has been obtained, dosage should be individualized according to patient tolerance and response. The lowest dose that provides continuing control of symptoms should be used for maintenance. {210}{211}

Usual adult prescribing limits
Doses larger than 2000 mg a day have not been studied and are not recommended. {210}{211}Usual pediatric dose
Safety and efficacy have not been established {210}.Usual geriatric dose
See Usual adult dose .Strength(s) usually available
U.S.—

500 mg (Rx) [Relafen{210}{211}]Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a well-closed container, {210} unless otherwise specified by manufacturer.Auxiliary labeling:
• Take with food.
• Take with a full glass of water.
• Avoid alcoholic beverages.

In arthritis, improvement in condition may occur within 2 weeks, but 2 to 4 weeks of continuous use on a regular basis may be required for maximum effectiveness.

Naproxen should be administered in the lowest effective dose to geriatric patients, patients with hepatic function impairment, or patients with renal function impairment (especially if creatinine clearance is < 20 mL per minute).

Note: During long-term administration, dosage may be adjusted according to patient response; lower doses may suffice. {01}{188}
For acute exacerbations of rheumatic disease, dosage may be increased to up to 1.5 grams per day for limited periods. Use of this high dose requires that the clinical benefit be increased sufficiently to offset the potential increased risk of adverse effects. {01}{188}

Anti-inflammatory (nonsteroidal) or
Analgesic (mild to moderate pain) or
Antidysmenorrheal
Oral, 500 mg initially, then 250 mg every six to eight hours as needed. {01}{188}

NAPROXEN SODIUM TABLETS USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 275 or 550 mg two times a day, morning and evening; or 275 mg in the morning and 550 mg in the evening. {142}

Note: During long-term administration, dosage may be adjusted according to patient response; lower doses may suffice.
If necessary, dosage may be increased to up to 1650 mg per day for short periods. The use of this higher dose requires that the clinical benefit be increased sufficiently to offset the potential increased risk. {142}

Anti-inflammatory (nonsteroidal) or
Analgesic (mild to moderate pain)
Oral, 550 mg initially, then 275 mg every six to eight hours as needed. {142}

Antidysmenorrheal
Oral, 550 mg initially, then 275 mg every six to eight hours as needed. {142}

Note: For patient self-medication (over-the-counter use) for pain, fever, or dysmenorrhea—Patients 12 years of age and older: Oral, 220 mg every eight to twelve hours while symptoms persist, or
Oral, 440 mg for the first dose only, followed by 220 mg twelve hours later and every eight to twelve hours thereafter as needed. {226}

Usual adult prescribing limits
For mild to moderate pain and
dysmenorrhea
Up to a total dose of 1375 mg daily. {142}

Note: For patient self-medication (over-the-counter use) for pain, fever, or dysmenorrhea—Not to exceed 2 tablets (220 mg each) in twenty-four hours for patients 65 years of age or older or 3 tablets in twenty-four hours for patients 12 to 65 years of age. {226}

Usual pediatric dose
Pediatric strength not available. It is recommended that naproxen oral suspension or tablets be administered instead. {39}Strength(s) usually available
U.S.—

NAPROXEN SODIUM EXTENDED-RELEASE TABLETSUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 750 to 1000 mg once a day in the morning or evening. {134}{189}{317}

Analgesic or
Antidysmenorrheal or
Anti-inflammatory (nonsteroidal)
Oral, 1000 mg once a day in the morning or evening {317}.

Note: For patients who require greater analgesic benefit, 1500 mg once a day for a limited period may be given. Thereafter, the daily dose should not exceed 1000 mg {317}.

Antigout
Oral, initially 1000 to 1500 mg once a day in the morning or evening, followed by 1000 mg once a day, until attack has subsided {317}.

Adult prescribing limits
1500 mg per day {317}.Usual pediatric dose
Safety and efficacy have not been established {317}.Usual geriatric dose
See Usual adult dose{317}.Strength(s) usually available
U.S.—

Usual adult prescribing limits
Total daily dose administered orally and rectally should not exceed 1.5 grams a day. The 1.5-gram daily dose is recommended only for short-term administration during acute exacerbations of rheumatic disease. Also, use of this high dose requires that the additional clinical benefit be sufficient to offset the potential increased risk of adverse effects. {01}Usual pediatric dose
Dosage has not been established.Strength(s) usually available
U.S.—
Not commercially available.

Precautions:
Carcinogenicity—Increased hepatic adenomas and carcinomas in male CD mice, but not in female CD mice or in rats.

Pregnancy/reproduction—Caused fetal malformations in rabbits with doses within the usual human therapeutic range, but not in mice or rats.

Pediatrics—Preliminary studies done in patients 3 to 16 years of age; elevated aspartate aminotransferase values occurred more frequently in patients treated for juvenile arthritis than for other forms of arthritis.

Geriatrics—Dosage adjustment not needed on basis of pharmacokinetic considerations. Studies showed increased occurrence of impaired renal function and of decreased hemoglobin concentration, but not of changes in hepatic function, in patients 60 years of age and older compared to younger adults.

Surgical—Recommended that oxaprozin be discontinued 1 to 2 weeks before elective surgery; may be more likely than most other NSAIDs to increase risk of perisurgical bleeding because of potent and prolonged inhibitory effect on platelet aggregation.

Osteoarthritis
Oral, 1200 mg per day, initially, although a lower dose of 600 mg per day may be sufficient for mild disease or for patients of low body weight. {163}

Note: Initial dosage must be individualized according to the severity of disease and patient variables such as body weight and renal function.
A single 1200-mg or 1800-mg loading dose may be administered to patients with normal renal function if necessary to speed the onset of action. {163}
An initial dose of 600 mg per day is recommended for patients with renal function impairment. If this dose is well tolerated, higher doses may be administered if needed. {163}
Doses of up to 1200 mg per day are usually administered once a day, but patients who are unable to tolerate a single dose of this size may tolerate divided doses. {163}
Very severe arthritis may require doses higher than 1200 mg per day, which should be administered in two or three divided doses. It is recommended that these higher doses be reserved for patients weighing more than 50 kg who have normal hepatic and renal function and a low risk of peptic ulceration and who have not experienced adverse effects with lower doses. {163}
After a beneficial response has been achieved, dosage should be reduced to the lowest dose that provides continuing control of symptoms. {163}

Usual adult prescribing limits
Oral, 1800 mg per day or 26 mg per kg of body weight per day, whichever is lower, in two or three divided doses. {163}Usual pediatric dose
Safety and efficacy in children have not been established. {163} However, one preliminary study in children 3 to 16 years of age used a starting dose of 10 mg per kg of body weight. The dose was increased to 20 mg per kg of body weight if necessary. {269}{270}Strength(s) usually available
U.S.—

Auxiliary labeling:
• Take with food.
• Take with a full glass of water.
• Avoid alcoholic beverages.

PHENYLBUTAZONE

Summary of Differences

Indications:
Recommended only for short-term treatment of severe arthritic conditions, gout, or calcium pyrophosphate deposition disease (pseudogout) in patients unresponsive to less toxic NSAIDs. Not recommended as initial therapy for any indication.

Because of its toxicity, phenylbutazone should be used in the minimum effective dosage and for the shortest possible time.

In geriatric patients, therapy should be limited to short periods, preferably not to exceed 1 week, because of the high risk of severe, possibly fatal, toxic reactions.

Phenylbutazone is generally better tolerated when administered with food to lessen gastric irritation.

If therapy is not effective within 1 week, the medication should be discontinued.

Edema may be dose-related and may be prevented in some patients by reducing the dosage.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.PHENYLBUTAZONE CAPSULES USPUsual adult dose
Rheumatoid arthritis1
or Osteoarthritis, acute attacks1
or Ankylosing spondylitis
[or Psoriatic arthritis]
Oral, 300 to 600 mg a day in three or four divided doses. {224}

Antigout agent
Oral, initially 400 mg as a single dose; then 100 mg every four hours for approximately four days or until a satisfactory response is obtained, with the duration of therapy not exceeding one week. {224}

Note: Some clinicians use a dose of 200 mg every four hours for approximately four days or until a satisfactory response is obtained, with the duration of therapy not exceeding two weeks.

Usual pediatric dose
Children up to 15 years of age—Use is not recommended. {224}Strength(s) usually available
U.S.—

PHENYLBUTAZONE TABLETS BUFFEREDUsual adult dose
See Phenylbutazone Capsules USP .Usual pediatric dose
Children up to 15 years of age—Use is not recommended. {224}Strength(s) usually available
U.S.—
Not commercially available.

Half-life—Elimination: 50 hours, although values ranging from 14 to 158 hours have been reported. Increased in patients with renal function impairment. May also be increased in elderly patients, especially females.

Because steady-state plasma concentrations are not reached for 7 to 12 days following initiation of therapy, the effectiveness of therapy with piroxicam should not be assessed for 2 weeks.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.PIROXICAM CAPSULES USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 20 mg once a day or 10 mg two times a day. {167}{168}

[Antidysmenorrheal]
Oral, 40 mg at the onset of symptoms on the first day only, then 20 mg once a day thereafter if necessary. {168}

Usual pediatric dose
Dosage has not been established.Strength(s) usually available
U.S.—

Oral Dosage FormsTENOXICAM TABLETSUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
and Anti-inflammatory (nonsteroidal)
Oral, 20 mg once a day, at the same time each day. For some patients, 10 mg once a day may be sufficient. The smallest effective dose should be used. {180}

Usual adult prescribing limits
20 mg per day. Higher doses may increase the risk of adverse effects without providing a significantly greater therapeutic response. {180}Usual pediatric dose
Children up to 16 years of age—Dosage has not been established. {180}Strength(s) usually available
U.S.—
Not commercially available.

TIAPROFENIC ACID TABLETSUsual adult dose
Rheumatoid arthritis
Oral, 600 mg a day in two or three divided doses. {48}{213}

Osteoarthritis
Oral, 600 mg a day in two or three divided doses, initially. After a satisfactory response has been obtained, dosage may be reduced. Some patients may be maintained on 300 mg a day in divided doses. {48}{213}

Usual adult prescribing limits
600 mg a day. {213}Usual pediatric dose
Safety and efficacy have not been established. {213}Strength(s) usually available
U.S.—
Not commercially available.

Improvement in condition may occur within 7 days, but 1 to 2 weeks of continuous use on a regular basis may be required for maximum effectiveness.

Oral Dosage Forms

Note: The dosing and strengths of the available dosage forms are expressed in terms of the free acid (not the sodium salt).TOLMETIN SODIUM CAPSULES USPUsual adult dose
Antirheumatic (nonsteroidal anti-inflammatory)
Initial: Oral, 400 mg (free acid) three times a day, preferably including a dose in the morning and a dose at bedtime. {216}

Maintenance: Rheumatoid arthritis
Oral, 600 mg to 1.8 grams (free acid) a day in three or four divided doses. {216}

Osteoarthritis
Oral, 600 mg to 1.6 grams (free acid) a day in three or four divided doses. {216}

Usual adult prescribing limits
Up to 2 grams (free acid) daily for rheumatoid arthritis or 1.6 grams (free acid) daily for osteoarthritis. {216}Usual pediatric dose
Antirheumatic (nonsteroidal anti-inflammatory)
Children up to 2 years of age: Dosage has not been established. {216}

Children 2 years of age and over: Initial—Oral, 20 mg (free acid) per kg of body weight a day in three or four divided doses. {216}

Maintenance—Oral, 15 to 30 mg (free acid) per kg of body weight a day in divided doses. {216}

Note: Doses higher than 30 mg (free acid) per kg of body weight per day have not been studied and therefore are not recommended. {216}

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